Kv1.3 inhibitors and their medical application

ABSTRACT

Disclosed are compounds within the scope of formula (II) or a salt or solvate thereof, medical uses involving them, and methods for their preparation

The present invention relates to inhibitors of the voltage-gatedpotassium channel Kv1.3, and their application for the treatment ofconditions in which Kv1.3 activity contributes to the disease state, inparticular for those mediated by activated effector memory T-cells.

BACKGROUND OF THE INVENTION

Voltage-gated potassium channels constitute the major ionic conductancedetected in both excitable and non-excitable cells and are importantplayers in cellular processes like regulation of ion balance, membranepotential, secretion and cell excitability (Lan et al., Cancer Biol.Ther. 2005, 4, 1342). Such events can mediate or trigger certainsignaling cascades, resulting in cellular processes of great diversity.

Certain cells of the immune system, for example, require a complexinterplay of different ion channels in order to convert a pathogenicstimulus into an appropriate action like proliferation and/or cytokinesecretion. Especially in T- and B-lymphocytes, this type of activationtriggers a calcium signal within the cell, which has to be maintainedfor an extended period in order to result in transcriptional activityand thus a completion of the activation program. For T-cells, theactivation via the T-cell receptor (TCR) triggers a signaling cascaderesulting in the calcium release from the endoplasmatic reticulum intothe cytosol. This release triggers the opening of the CRAC (Ca²⁺-releaseactivated channel), enabling a strong calcium influx into the cell. Formaintaining such a calcium influx for an extended period of time, whichis required for an efficient T-cell response on a cellular level,potassium has to be released from the cytosol. For this purpose, T-cellsare equipped with two potassium channels, the KCa3.1(IK-1), which iscalcium-gated and thus opens upon increasing cytosolic calciumconcentrations, and Kv1.3, which is voltage-gated and opens due to thedepolarization of the membrane potential caused by the calcium influx.Both act together for potassium efflux, now allowing for further calciuminflux via CRAC into the cell. This interplay of CRAC, IK-1 and Kv1.3 iscrucial for an activation of lymphocytes to result in proliferationand/or cytokine production (Lewis, Annu. Rev. Immunol. 2001, 19, 497;Vig et al., Nat. Immunol. 2009, 10, 21; Feske et al., Nat. Rev. Immunol.2012, 12, 532).

Different T- and B-cell subsets display different expression numbers ofIK-1 and Kv1.3, of which class-switched memory B-cells and repeatedlyactivated effector memory T-cells (T_(EM) cells; CD⁴⁺ T-cells and CD⁸⁺T-cells) are dominated by Kv1.3. These lymphocyte subsets are of theKv1.3^(highIK-)1^(low) phenotype, in which Kv1.3 expression numbers of1000 to 2900 channels per cell were found, whereas IK-1 channel numbersin these cells are clearly below 100. In contrast, other activated T-and B-cell subsets display rather similar expression numbers for Kv1.3and IK-1 of several hundred per cell each, and in some instances evenwith a favour of IK-1 (for further information see the review articleslisted below).

Inhibition of Kv1.3 is thus effective in decreasing lymphocyteproliferation and/or cytokine production in lymphocytes of theKv1.3^(highIK-)1^(low) phenotype, whereas other lymphocyte subsets areexpected not to respond significantly (for further information see thereview articles listed in the following paragraph and Shah et al., Cell.Immunol. 2003, 22, 100).

Several review articles deal with Kv1.3 channel architecture,distribution in human tissues and cell types and the pharmacologicalpotential in its inhibition to treat diseases, including: Wulff et al.,Chem. Rev. 2008, 108, 1744; Lam et al., Drug Dev. Res. 2011, 72, 573;Wang et al., Pharmacother. 2013, 33, 515.

T_(EM) cells of the Kv1.3^(highIK-)1^(low) phenotype have beenpostulated to be the crucial subset of disease-mediating lymphocytes inT-cell driven autoimmune disorders (for further information see thereview articles listed in the preceding paragraph). This has beendirectly demonstrated within isolates from human patients with, e.g.,Type 1 diabetes (T1D; PNAS 2006, 103, 17414), rheumatoid arthritis (RA;PNAS 2006, 103, 17414), multiple sclerosis (MS; J. Clin. Invest. 2003,111, 1703; PNAS 2005, 102, 11094), psoriasis and psoriatic arthritis (J.Invest. Dermatol. 2011, 131, 118; J. Autoimmunity 2014, 55, 63), andanti-glomerular basement membrane glomerulonephritis (Am. J. Physiol.Renal Physiol. 2010, 299, F1258). In PBMCs isolated from patients withacute coronary syndrome (ACS), the number of CD4⁺CD28^(null) T-cells wassignificantly higher than in healthy controls and directly correlatedwith hs-CRP levels in these patients. This disease relevant T-cellsubset significantly overexpressed Kv1.3 in these patients (Huang etal., J. Geriatric Cardiol. 2010, 7, 40) and was identified to consistmainly of T_(EM) cells (Xu et al., Clin. Immunol. 2012, 142, 209).Within induced sputum form asthma patients, increased levels of TEMcells were identified, being of the Kv1.3high phenotype (Koshy et al.,J. Biol. Chem. 2014, 289, 12623).

T_(EM) cells have also been reported to be important contributors todisease development and/or progression in chronic diseases likeanti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitis(AAV; Abdulahad et al., Arthritis Res. Ther. 2011, 13, 236; Wilde etal., Arthritis Res. Ther. 2010, 12, 204), systemic lupus erythematosus(SLE; Dolff et al., Ann. Rheum. Dis. 2010, 69, 2034), Graft-versus-Hostdisease (Yamashita et al., Blood 2004, 103, 3986; Zhang et al., J.Immunol. 2005, 174, 3051; Beeton et al., Neuroscientist 2005, 11, 550),Inflammatory Bowel Diseases (IBDs; Kanai et al., Am. J. Physiol.Gastrointest. Liver Physiol. 2006, 290, G1051) including Crohn's disease(de Tena et al., J. Clin. Immunol. 2004, 24, 185; Beeton et al.,Neuroscientist 2005, 11, 550), autoimmune thyroiditis and Hashimotodisease (Seddon et al., J. Exp. Med. 1999, 189, 279; Beeton et al.,Neuroscientist 2005, 11, 550), Uveitis including Pars planitis(Pedroza-Seres et al., Br. J. Ophthalmol. 2007, 91, 1393; Oh et al., J.Immunol. 2011, 187, 3338; Beeton et al., Neuroscientist 2005, 11, 550),alopecia areata (Gilhar et al., J. Invest. Dermatol. 2013, 133, 2088),vitiligo, Pemphigus foliaceus, inclusion body myositis, dermatomyositis,and scleroderma (Beeton et al., Neuroscientist 2005, 11, 550).Furthermore, the important role of class-switched memory B-cells fordisease pathogenesis has also been described for T1D, RA and MS (Wulffet al., J. Immunol. 2004, 173, 776), Grave and Hashimoto disease, andSjögren syndrome (Beeton et al., Neuroscientist 2005, 11, 550). Inaddition, Kv1.3 inhibitors have been reported to inhibitCD8+T_(EM)/T_(EMRA) cell differentiation and proliferation and theirGranzyme B release, and linked to a reduction of their neurotoxicity andthus to a potential treatment of neuroinflammatory disorders like MS(Wang et al., PLoS One 2012, 7, e43950; Hu et al., PLoS One 2013, 8,e54267).

Furthermore, Kv1.3 has been identified in other cell types of the immunesystem like macrophages (DeCoursey et al., J. Membrane Biol. 1996, 152,141; Villalonga et al., Biochem. Biophys. Res. Commun. 2007, 352, 913),microglia (Eder, Am. J. Physiol. Cell Physiol. 1998, 275, C327; Menteyneet al., PLoS One 2009, 4, e6770; Pannasch et al., Mol. Cell. Neurosci.2006, 33, 401), dendritic cells (Zsiros et al., J. Immunol. 2009, 183,4483), non-adherent natural killer cells (Koshy et al., PLoS One 2013,8, e76740), in cells of the CNS like human neural progenitor cells (Wanget al., J. Neurosci. 2010, 30, 5020; Peng et al., J. Neurosci. 2010, 30,10609), postganglionic sympathetic neurons (Doczi et al., Am. J.Physiol. Regul. Integr. Comp. Physiol. 2008, 295, 733), select centraland peripheral neurons, neurons in the nucleus of the solitary tract(Ramirez-Navarro et al., J. Neurophysiol. 2011, 105, 2772), andoligodendrocytes (Tegla et al., Exp. Mol. Pathol. 2011, 91, 335.). Withregard to microglia, their neurotoxic effect upon activation with eitherHIV-1 glycoprotein gp120 or HIV-1 Tat protein was abrogated upontreatment with Kv1.3 inhibitors, which underlines their potential fortherapy of HIV-1-associated neurocognitive disorders (HAND) and otherinflammation-mediated neurological disorders (Liu et al., Cell DeathDis. 2012, 3, e254; and PLoS One 2013, 8, e64904). Furthermore, primingof microglia by amyloid-r3 resulting in reactive oxygen species (ROS)production upon secondary stimulation was inhibited by treatment withKv1.3 inhibitors, thus rendering Kv1.3 channels potential targets toreduce microglia-induced oxidative stress in Alzheimer's disease(Schilling et al., J. Cell. Physiol. 2011, 226, 3295). Furthermore,Kv1.3 inhibition was shown to decrease microglia migration(Nutile-McMenemy et al., J. Neurochem. 2007, 103, 2035). Concerningmacrophages, Kv1.3 inhibitors were shown to e.g. modulatecholesterol-metabolism-associated molecules thus inhibiting macrophages'differentiation into foam cells, which represents a strategy for thetreatment of atherosclerosis (also known as arteriosclerotic vasculardisease or ASVD) (Yang et al., J. Lipid Res. 2013, 54, 34).

Kv1.3 has also been identified in retinal ganglion cells (Koeberle etal., Cell Death Diff. 2010, 17, 134), platelets and megakaryocytes(McCloskey et al., J. Physiol. 2010, 588, 1399; Emerson, J. Physiol.2010, 588, 1809), and tumorigenic human mammary epithelial cells (Janget al., BMB reports 2009, 42, 535), human ovarian cancer cells likeSKOV3 (Weng et al., Frog. Mod. Biomed. 2011, 11, 2053), human lungadenocarcinoma cells A549 (Jang et al., Eur. J. Pharmacol. 2011, 651,26), brown adipose tissue and hepatocytes (Upadhyay et al., PNAS 2013,110, E2239) and skeletal muscle cell lines (Hamilton et al., J. Physiol.Sci. 2014, 64, 13). In addition, Kv1.3 was reported to represent apotential sensor of metabolism within the olfactory bulb (Fadool et al.,PLoS One 2011, 6, e24921; Tucker et al., J. Physiol. 2013, 10, 2541 andJ. Neuroendocrinol. 2012, 24, 1087). Furthermore, Kv1.3 was identifiedin the inner membrane of mitochondria, where they are involved in theintrinsic apoptosis pathway, and their inhibition was evaluated for thetreatment of chronic lymphocytic leukemia (B-CLL) (Leanza et al.,Leukemia 2013, 27, 1782), osteosarcoma, neuroblastoma and melanoma(Leanza et al., EMBO Mol. Med. 2012, 4, 577; Wu et al., Int. J. Mol.Sci. 2013, 14, 19245; Leanza et al., Curr. Pharmaceut. Design 2014, 20,189), and suggested for the depletion of tumor-associated macrophages(Leanza et al., Curr. Med. Chem. 2012, 19, 5394). Inhibitors of Kv1.3were also shown to potently suppress migration and proliferation ofvascular smooth muscle cells, which might represent a new principle forthe treatment of restenosis/neointimal hyperplasia (Jackson,Arterioscler. Thromb. Vasc. Biol. 2010, 30, 1073; Cheong et al.,Cardiovasc. Res. 2011, 89, 282; Olschewski, Cardiovasc. Res. 2011, 89,255; Cidad et al., Arterioscler. Thromb. Vasc. Biol. 2012, 32, 1299;Ishii et al., Free Rad. Biol. Med. 2013, 65, 102; Cidad et al., PflugersArch. Eur. J. Physiol.; DOI 10.1007/s00424-014-1607-y).

Kv1.3 expression has also been shown to be a potential disease marker inbiopsies of inflamed mucosa from ulcerative colitis patients andcorrelated with certain cytokine expression levels (Hansen et al., J.Crohn's Col. 2014, 8, 1378).

A Kv1.3 inhibitor has been shown to decrease activation levels ofTh2-cells and cytotoxic CD8⁺ T-cells in PBMCs from patients with acuteischemic stroke (AIS), potentially reducing its unwanted clinicalconsequences (Folyovich et al., CNS Neurol. Diorders Drug Targets 2014,13, 801).

For CD4⁺ T lymphocytes from PBMCs isolated from patients with essentialhypertension, a chronic low-grade inflammatory disease, increased Kv1.3expression levels compared to undiseased control group were reported(Li, Exp. Clin. Cardiol. 2014, 20, 5870).

Efficacy of Kv1.3 inhibitors has been reported in relevant animal modelsfor autoimmune diseases like Psoriasis, MS, alopecia areata, rheumatoidarthritis, type I diabetes, allergic and irritiant contact dermatitis(Azam et al., J. Invest. Dermatol. 2007, 127, 1419; Ueyama et al., Clin.Experiment. Dermatol. 2013, 38, 897; Kundu-Raychaudhuri et al., J.Autoimmunity 2014, 55, 63), anti-glomerular basement membraneglomerulonephritis (as a cause of rapidly progressiveglomerulonephritis), and also for asthma, chronic kidney disease, renalfibrosis in chronic renal failure and end-stage renal disease (Kazama,J. Physiol. Sci. 2015, 65, 25; Kazama et al., Int. J. Nephrol. 2012,article ID 581581), and for melanoma, obesity, insulin resistance, andneuroprotection and neurorestoration (Peng et al., Neuro-Oncology 2014,16, 528). A Kv1.3 inhibitor was reported to reduce tumor volume in axenograft model using the human lung adenocarcinoma cells A549 (Jang etal., Eur. J. Pharmacol. 2011, 651, 26), and to decrease intimalhyperplasia formation, indicating a therapeutic potential againstrestenosis (Cidad et al., Cardiovasc. Drugs Ther. 2014, 28, 501). Kv1.3inhibition prevented plaque formation and decreased exocytosis ofcytoplasmic granules from CD4⁺CD28^(null) T-cells in a rat model forartherosclerosis, revealing a potential for suppression of thedevelopment of atherosclerosis and prevention of acute coronary syndrome(Wu et al., Heart Vessels 2015, 30, 108).

A combination of an IK-1 inhibitor and a Kv1.3 inhibitor has been shownto be effective in preventing transplant rejection in an animal model(Grgic et al., Transplant. Proc. 2009, 41, 2601). A similar effect wasreported for the Kv1.3 inhibitor Correolide C within a vascularizedcomposite allotransplantation (VCA) model (Hautz et al., Transplant.Int. 2013, 26, 552). Kv1.3 inhibition has also been shown to beeffective in preventing T-cell mediated inflammatory bone resorptiondisease (Valverde et al., J. Bone Miner. Res. 2004, 19, 155).

Certain small molecule Kv1.3 inhibitors have been reported. For a briefoverview, cf. Wulff et al., Chem. Rev. 2008, 108, 1744; and Wulff etal., Nat. Rev. Drug Disc. 2009, 8, 982. Furthermore, certain compoundswere published as Kv1.3 inhibitors, belonging to scaffolds likesulfonamides (WO2011/073269, WO2011/073273, WO2011/073277,WO2010/130638, WO2010/023448), spiro compounds (WO2010/066840),pyrazoles and imidazoles (WO2007/020286), dioxidobenzothiazols (Haffneret al., Bioorg. Med. Chem. Lett. 2010, 20, 6983 and 6989; WO2005/11304),and phenanthridines (Pegoraro et al., Bioorg. Med. Chem. Lett. 2009, 19,2299 and 2011, 21, 5647).

Out of this set of compounds, especially certain khellinones (Baell etal., J. Med. Chem. 2004, 47, 2326; Harvey et al., J. Med. Chem. 2006,49, 1433; Cianci et al., Bioorg. Med. Chem. Lett. 2008, 18, 2055;WO03/078416; WO2006/096911; WO2008/040057; WO2008/040058; WO2009/043117;WO2009/149508) and the psoralen derivative PAP-1 (Vennekamp et al., Mol.Pharmacol. 2004, 65, 1364; Schmitz et al., Mol. Pharmacol. 2005, 68,1254; Bodendiek et al., Eur. J. Med. Chem. 2009, 44, 1838;WO2006/041800; U.S. Pat. No. 7,772,408) have been evaluated with regardto their potential as Kv1.3 inhibitors.

Furthermore, certain Kv1.3 inhibitors have been described in the fieldof cardiovascular pathologies, particularly in the field of diseasesderived from hyperplasia of the tunica intima (WO2010/040803) and forapplication in neurodegenerative diseases, in particular forneuroprotection and stimulation of neural growth (WO2007/139771) andreduction of microglia-mediated neurotoxicity (WO2012/170917). Kv1.3inhibitors have also been reported to affect weight control, control ofbody fat and food intake and thus for treating obesity, diabetes andinsulin insensitivity (WO2002/100248). Furthermore, a combinationtreatment of a Kv1.3 inhibitor with a pre-implantation factor peptidefor the treatment of intracellular damage resulting from e.g. Lymedisease, cardiovascular disease, duodenal peptic ulcer, atherosclerosisor tuberculosis was described (WO2012/119072). WO2013/052507 describestargeting the Kv1.3 channel as a treatment for obesity andobesity-related disorders.

Syntheses of certain 5-phenyl-furo[3,2-g]coumarin (that is4-phenyl-psoralen) derivatives have been described in the literature,usually involving a Pechmann cyclization and a McLeod's reaction. Cf.for example Ansary, Bull. Fac. Pharm. Cairo Univ. 1998, 36, 85; Garazdet al., Chem. Nat. Comp. 2000, 36, 478; Garazd et al., Chem. Nat. Comp.2002, 38, 539; Traven et al., Heterocyclic Commun. 1997, 3, 339;Pardanani et al., J. Ind. Chem. Soc. 1969, 46, 1014. A specific routefor inverting the anellation order of the lacton-ring and the furan isdescribed in Kawase et al., Bull. Chem. Soc. Jpn. 1978, 51, 1907-1908;Zhang et al., Eur. J. Med. Chem. 2010, 45, 5258. A synthetic routetowards certain furo[3,2-g]quinolin-7(8H)-one, thieno[3,2-g]coumarin,6H-chromeno[6,7-d]oxazol-6-one (i.e. oxazolocoumarin) and 8-azapsoralenderivatives is described in Guiotto et al., Il Farmaco 1995, 50, 479;Chilin et al., Gazz. Chim Ital. 1988, 118, 513, and Rodighiero et al.,J. Heterocyclic Chem. 1998, 35, 847, however, these compounds were allequipped only with methyl substituents.

Certain specific psoralens, and xanthotoxin in particular, have beendescribed for their potential photobiological activities and for theiruse in photochemotherapy (PUVA=psoralen+UVA irraditation) (Pathak etal., J. Invest. Dermatol. 1959, 32, 255; Juettermann et al., Farmaco,Edizione Scientifica 1985, 40, 3; Toth et al., J. Photochem. Photobiol.B Biol. 1988, 2, 209; Nofal et al., Pakistan J. Scientific Ind. Res.1990, 33, 148; Tuveson et al., Photochem. Photobiol. 1992, 56, 341;Becker et al., J. Chem. Soc. Faraday Trans. 1993, 89, 1007; Körner,Arch. Pharm. Med. Chem. 2002, 5, 187). Such investigations have alsobeen performed for certain 5-phenyl-furo[3,2-g]coumarin (that is4-phenyl-psoralen) derivatives: Farag, Eur. J. Med. Chem. 2009, 44, 18;Lown et al., Bioorg. Chem. 1978, 7, 85; Ansary, Bull. Fac. Pharm. CairoUniv. 1998, 36, 85. For specific linear furo[3,2-g]quinolone,thieno[3,2-g]coumarin, 8-azapsoralen and thieno-[3,2-g]-8-aza-coumarinderivatives, such a photobiological effect has also been investigated:Guiotto et al., J. Heterocyclic Chem. 1989, 26, 917; Guiotto et al., IlFarmaco 1995, 50, 479; Aubin et al., J. Invest. Dermatol. 1991, 97, 50and 995; Vedaldi et al., Il Farmaco 1991, 46, 1407.

Furthermore, certain 5-phenyl-furo[3,2-g]coumarins are reported to havepotential in treating or preventing diseases caused or mediated byHelicobacter pylori (CN102091067, Zhang et al., Eur. J. Med. Chem. 2010,45, 5258), in treating diabetes mellitus and complicating diseasesthereof (CN101307056), for controlling coccids (JP63057590), and asinhibitors of NFkB and its functions in cystic fibrosis (Piccagli etal., Bioorg. Med. Chem. 2010, 18, 8341).

With regard to furoquinolones, certain biological activities have onlybeen reported for 4-methylbenzofuro[3,2-g]quinolin-2(1H)-one: Asinhibitor of FKBP52-enhanced steroid receptor activity (WO2011/034834),as inhibitor of ABCG2 protein for a method of enhancing treatment oftumor cells with a chemotherapeutic agent (WO2009/061770), and tostimulate or inhibit the binding to and lipid movements mediated bySR-BI and redirect uptake and metabolism of lipids and cholesterol bycells (WO2004/032716).

With regard to the treatment of inflammatory diseases driven byrepeatedly activated T_(EM) cells, especially autoimmune diseases,general immunosuppressants are utilized in currently applied treatmentregimens (e.g. mycophenolate mofetil, cyclophosphamide, cyclosporine A,azathioprine, etc.) resulting in a general suppression of lymphocytes,thus increasing the risk for opportunistic infections. Furthermore,longterm treatment often results in side effects reducing the overallcompliance (e.g. skin atrophy and enhanced risk of osteoporosis withglucocorticoid treatment, increased risk of skin cancer andrhabdomyolysis upon topical tacrolimus treatment, nausea and vomitingwith cyclophosphamide and cyclosporine A). Recent approvals ofmedicaments for the treatment of such diseases include several biologics(e.g. Alefacept, Natalizumab, Adalimumab, Ustekinumab, Belimumab), whichdisplay a potential for a general side effect profile known for suchdrugs like sensitization, anaphylactic shock, resistance, and againoften showed an enhanced risk for opportunistic infections.

There is, therefore, a need for new small molecule medicaments which,compared with the aforementioned therapeutics, are particularly moreselective towards specific cell subsets of the immune system andparticularly avoid the aforementioned adverse effects, in particular inthe therapy of the above medical conditions.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found that such a small molecule medicament can berepresented by Kv1.3 inhibitors, which, compared with the aforementionedtherapeutics, are particularly more selective towards Kv1.3^(high)phenotype cells, particularly class-switched memory B-cells and/oreffector memory T-cells which are of the Kv1.3^(high) phenotype, andparticularly avoid the aforementioned adverse effects, in particular inthe therapy of the above medical conditions.

Embodiments of the present invention are detailed in the followingitems:

-   1. A compound of the general formula (II) or a salt or solvate    thereof,

-   -   wherein    -   A¹ is selected from the group consisting of N and C—R⁸;    -   A² is selected from the group consisting of N and C—R³;    -   A³ is selected from the group consisting of N and C—R⁹;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, halogen, (C₁-C₃)alkoxy, and (C₁-C₃)haloalkyl;    -   R² is selected from the group consisting of hydrogen, halogen,        and (C₁-C₃)alkyl;    -   R³ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, NR⁴R⁵, (C₁-C₃)alkyl-NR⁴R⁵, and cyano, wherein R⁴        and R⁵ are independently selected from the group consisting of        hydrogen, (C₃-C₅)cycloalkyl, (C₃-C₅)heterocycloalkyl and        (C₁-C₃)alkyl, or    -   R⁴ and R⁵ together with the nitrogen atom to which they are        attached form a 5- to 7-membered heterocyclic ring optionally        comprising in addition to the aforementioned nitrogen atom a        further heteroatom group selected from the group consisting of O        and NR⁶, wherein R⁶ is selected from the group consisting of        hydrogen, methyl, acetyl and formyl;    -   Y is selected from the group consisting of O and S;    -   R⁸ is selected from the group consisting of (C₁-C₄)alkyl,        (C₃-C₅)cycloalkyl and (C₃-C₅)heterocycloalkyl; and    -   R⁹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl and (C₁-C₃)alkoxy;    -   with the proviso that the following compounds are excluded:    -   3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        2,3,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        2,3-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        3-ethyl-9-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        3-(tert-butyl)-5-phenyl-7H-furo[3,2-g]chromen-7-one,        3-(tert-butyl)-9-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        and 2-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one.

-   2. A compound according to item 1 or a salt or solvate thereof,    wherein    -   R¹ is selected from the group consisting of hydrogen, methyl,        chloro, fluoro, methoxy, ethoxy and trifluoromethyl;    -   R² is selected from the group consisting of hydrogen, bromo and        methyl;    -   R³ is selected from the group consisting of hydrogen, methyl,        morpholinyl, morpholinomethyl, N-methylaminomethyl,        N,N-dimethylaminomethyl and cyano;    -   R⁸ is selected from the group consisting of methyl, ethyl and        cyclopropyl; and    -   R⁹ is selected from the group consisting of hydrogen, methyl and        methoxy.

-   3. A compound according to item 1 or 2 or a salt or solvate thereof,    wherein    -   R² is selected from the group consisting of hydrogen and methyl;        and R³ is selected from the group consisting of hydrogen,        morpholinyl, morpholinomethyl, N,N-dimethylaminomethyl and        cyano.

-   4. A compound according to any of items 1 to 3 or a salt or solvate    thereof, wherein Y is S, or Y is O, and if Y is O, at least one of    A¹, A² or A³ is N.

-   5. A compound according to any of items 1 to 3 or a salt or solvate    thereof, wherein A¹ is C—R⁸; A² is C—R³; A³ is C—R⁹; and Y is O.

-   6. A compound according to any of items 1 to 5 or a salt or solvate    thereof, wherein at least one of the following conditions is    fulfilled: 1) R² is halogen, 2) R³ is selected from the group    consisting of NR⁴R⁵ and cyano, 3) A⁴ or A⁵ or A⁶ is N.

-   7. A compound according to any of items 1 to 6 or a salt or solvate    thereof, wherein one of A⁴ and A⁵ and A⁶ is N and the others are    selected from the group consisting of N and C—R¹.

-   8. A compound according to any of items 1 to 7 or a salt or solvate    thereof, wherein R⁸ is methyl; R⁹ is methyl; R¹ is selected from the    group consisting of hydrogen and methoxy; R² is selected from the    group consisting of hydrogen and methyl; and R³ is selected from the    group consisting of hydrogen, methyl and N-methylaminomethyl.

-   9. A compound according to item 1, which is selected from the group    consisting of the compounds listed as examples of the present    invention in Table 1 or a salt or solvate thereof.

-   10. A pharmaceutical composition comprising a compound according to    any of items 1 to 9 and a pharmaceutically acceptable carrier or    diluent.

-   11. A compound according to any of items 1 to 9 for use in the    treatment of diseases or medical conditions.

-   12. Use of a compound according to any of items 1 to 9 for the    manufacture of a pharmaceutical composition for treating diseases or    medical conditions.

-   13. The compound according to item 10 or the use according to item    11, wherein said disease or medical condition is a disease or    medical condition wherein the inhibition of the voltage-gated    potassium channel Kv1.3 is beneficial.

-   14. The compound or use according to item 13, wherein said disease    or medical condition is selected from the group consisting of    psoriasis, psoriatric arthritis, autoimmune thyroiditis, Hashimoto's    disease, Grave's disease, rheumatoid arthritis, vitiligo, Crohn's    disease, ulcerative colitis, inflammatory bowel disease, ankylosing    spondylitis (Morbus Bechterew), periodontal disease, diabetes type    I, multiple sclerosis, systemic lupus erythematosus, anti-glomerular    basement membrane glomerulonephritis, rapidly progressive    glomerulonephritis, advanced chronic renal failure, chronic kidney    disease, renal fibrosis, uveitis, Pars planitis, asthma, Pemphigus    foliaceus, inclusion body myositis, dermatomyositis, scleroderma,    Behcet disease, atopic dermatitis, allergic and irritant contact    dermatitis, Lichen planus, Sjögren's syndrome,    Graft-versus-Host-Reaction, Host-versus-Graft-Reaction, transplant    rejection, end-stage renal disease, vascularized composite    allotransplantation rejection, alopecia areata, inflammatory bone    resorption disease, anti-neutrophil cytoplasmic    autoantibody-associated vasculitis, osteoarthritis, diseases    associated with intimal hyperplasia, breast cancer, leukemia,    chronic lymphocytic leukemia, human lung adenocarcinoma, cutaneous    T-cell lymphoma, osteosarcoma, neuroblastoma, ovarian cancer and    melanoma, neuroinflammatory disorders, neurodegeneration,    HIV-1-associated neurocognitive disorders (HAND), microglia-induced    oxidative stress in Alzheimer's disease, obesity, and insulin    resistance, restenosis/neointimal hyperplasia, atherosclerosis    (arteriosclerotic vascular disease or ASVD), acute coronary    syndrome, acute ischemic stroke, hypertension.

-   15. A method for producing a compound according to item 1, wherein    A¹ is C—R⁸ and A² is selected from the group consisting of CH and N;    and wherein said method is characterized by the following    conversion:

-   -   wherein A³, A⁴, A⁵, A⁶, R², R⁸ and Y are as defined above;    -   W is selected from the group consisting of

wherein R⁸ is as defined above, and

-   -   W² is selected from the group consisting of CH₂, CH—CH₃,        C(CH₃)₂, CH—CH₂—CH₃, C(CH₃)—CH₂—CH₃, CH—CH(CH₃)—CH₃, and        CH—CH₂—CH₂—CH₃, and said method further comprises the step of        transition metal mediated intramolecular alkylation at the        position marked with an asterisk in the above formula II′;    -   or W is hydrogen and said method further comprises transition        metal mediated acylation at the position marked with an asterisk        in the above formula II′ using

-   -   wherein W² is as defined above and Rc is (C₁-C₄)alkyl; followed        by cyclization using hydroxylamine.

Further embodiments of the present invention are detailed in thefollowing items:

-   B1. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is selected from the group consisting of N and C—R⁸;    -   A² is selected from the group consisting of N and C—R³;    -   A³ is selected from the group consisting of N and C—R⁹;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen, methyl,        chloro, fluoro, methoxy, ethoxy and trifluoromethyl;    -   R² is selected from the group consisting of hydrogen, bromo and        methyl;    -   R³ is selected from the group consisting of hydrogen, methyl,        morpholinyl, morpholinomethyl, N-methylaminomethyl,        N,N-dimethylaminomethyl and cyano;    -   Y is selected from the group consisting of O and S; R⁸ is        selected from the group consisting of methyl, ethyl and        cyclopropyl;    -   R⁹ is selected from the group consisting of hydrogen, methyl and        methoxy;    -   with the proviso that the following compounds are excluded:    -   3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        2,3,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        2,3-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        3-ethyl-9-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one, and        2-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one.-   B2. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is selected from the group consisting of N and C—R⁸;    -   A² is selected from the group consisting of N and C—R³;    -   A³ is selected from the group consisting of N and C—R⁹;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen, methyl,        chloro, fluoro, methoxy, ethoxy and trifluoromethyl;    -   R² is selected from the group consisting of hydrogen and methyl;    -   R³ is selected from the group consisting of hydrogen, methyl,        morpholinyl, morpholinomethyl, N-methylaminomethyl,        N,N-dimethylaminomethyl and cyano;    -   Y is selected from the group consisting of O and S; R⁸ is        selected from the group consisting of methyl, ethyl and        cyclopropyl;    -   R⁹ is selected from the group consisting of hydrogen, methyl and        methoxy;    -   with the proviso that the following compounds are excluded:    -   3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        2,3,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        2,3-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        3-ethyl-9-methyl-5-phenyl-7H-furo [3,2-g]chromen-7-one, and        2-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one.-   B3. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is C—R⁸; A² is C—R³; A³ is C—R⁹; Y is O;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, halogen, (C₁-C₃)alkoxy and (C₁-C₃)haloalkyl;    -   R² is selected from the group consisting of hydrogen, halogen        and (C₁-C₃)alkyl;    -   R³ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, NR⁴R⁵, (C₁-C₃)alkyl-NR⁴R⁵ and cyano;    -   wherein R⁴ and R⁵ are independently selected from the group        consisting of hydrogen, (C₃-C₅)cycloalkyl,        (C₃-C₅)heterocycloalkyl, (C₁-C₃)alkyl, or R⁴ and R⁵ together        with the nitrogen atom to which they are attached form a 5- to        7-membered heterocyclic ring optionally comprising in addition        to the aforementioned nitrogen atom a further heteroatom group        selected from the group consisting of O and NR⁶, wherein R⁶ is        selected from the group consisting of hydrogen, methyl, acetyl        and formyl;    -   R⁸ is selected from the group consisting of (C₁-C₄)alkyl,        (C₃-C₅)cycloalkyl and (C₃-C₅)heterocycloalkyl;    -   R⁹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl and (C₁-C₃)alkoxy; with the proviso that the        following compounds are excluded:    -   3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        2,3,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        2,3-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        3-ethyl-9-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        3-(tert-butyl)-5-phenyl-7H-furo[3,2-g]chromen-7-one, and        3-(tert-butyl)-9-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one.-   B4. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is C—R⁸; A² is C—R³; A³ is C—R⁹; Y is O;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen, methyl,        chloro, fluoro, methoxy, ethoxy and trifluoromethyl;    -   R² is selected from the group consisting of hydrogen, bromo and        methyl;    -   R³ is selected from the group consisting of hydrogen, methyl,        morpholinyl, morpholinomethyl, N-methylaminomethyl,        N,N-dimethylaminomethyl and cyano;    -   R⁸ is selected from the group consisting of methyl, ethyl and        cyclopropyl;    -   R⁹ is selected from the group consisting of hydrogen, methyl and        methoxy; with the proviso that the following compounds are        excluded:    -   3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        2,3,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        2,3-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one, and        3-ethyl-9-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one.-   B5. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is C—R⁸; A² is C—R³; A³ is C—R⁹; Y is O;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen, methyl,        chloro, fluoro, methoxy, ethoxy and trifluoromethyl;    -   R² is selected from the group consisting of hydrogen and methyl;    -   R³ is selected from the group consisting of hydrogen,        morpholinyl, morpholinomethyl, N,N-dimethylaminomethyl and        cyano;    -   R⁸ is selected from the group consisting of methyl, ethyl and        cyclopropyl;    -   R⁹ is selected from the group consisting of hydrogen, methyl and        methoxy;    -   with the proviso that the following compounds are excluded:    -   3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,        3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one, and        3-ethyl-9-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one.-   B6. A compound selected from the group consisting of:-   5-(2-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,-   5-(3-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,-   5-(2-chlorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,-   3,9-dimethyl-5-(3-(trifluoromethyl)phenyl)-7H-furo[3,2-g]chromen-7-one,-   5-(2-fluorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,-   5-(3-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,-   5-(2-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,-   5-(2-fluorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,-   3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,-   5-(2-ethoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,-   5-(2-chlorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,-   3,9-dimethyl-2-morpholino-5-phenyl-7H-furo[3,2-g]chromen-7-one,-   3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,-   3,9-dimethyl-2-(morpholinomethyl)-5-phenyl-7H-furo[3,2-g]chromen-7-one,-   2-((dimethylamino)methyl)-3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,-   3-ethyl-6,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,-   3-methyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one,-   3-methyl-5-(m-tolyl)-7H-furo[3,2-g]chromen-7-one,-   5-(2-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,-   5-(3-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,-   5-(2-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,-   5-(3-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,-   9-methoxy-3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,-   3-cyclopropyl-9-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,-   3-cyclopropyl-6,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,-   3,9-dimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,-   3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,-   2-((dimethylamino)methyl)-3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,-   3,6,9-trimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,-   3,9-dimethyl-5-(pyridin-2-yl)-7H-furo[3,2-g]chromen-7-one,-   3,9-dimethyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one,-   5-(2-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,    and    5-(4-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,    or a salt or solvate thereof.-   B7. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is C—R⁸; A² is C—R³; A³ is C—R⁹; Y is O;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, halogen, (C₁-C₃)alkoxy and (C₁-C₃)haloalkyl;    -   R² is selected from the group consisting of hydrogen, halogen        and (C₁-C₃)alkyl;    -   R³ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, NR⁴R⁵, (C₁-C₃)alkyl-NR⁴R⁵ and cyano;    -   wherein R⁴ and R⁵ are independently selected from the group        consisting of hydrogen, (C₃-C₅)cycloalkyl,        (C₃-C₅)heterocycloalkyl, and (C₁-C₃)alkyl, or R⁴ and R⁵ together        with the nitrogen atom to which they are attached form a 5- to        7-membered heterocyclic ring optionally comprising in addition        to the aforementioned nitrogen atom a further heteroatom group        selected from the group consisting of O and NR⁶, wherein R⁶ is        selected from the group consisting of hydrogen, methyl, acetyl        and formyl;    -   R⁸ is selected from the group consisting of (C₁-C₄)alkyl,        (C₃-C₅)cycloalkyl, and (C₃-C₅)heterocycloalkyl;    -   R⁹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl and (C₁-C₃)alkoxy with the proviso that at least        one of the following conditions is fulfilled:    -   1) R² is halogen, or    -   2) R³ is selected from the group consisting of NR⁴R⁵ and cyano,    -   3) A⁴ or A⁵ or A⁶ is N.-   B8. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is C—R⁸; A² is C—R³; A³ is C—R⁹; Y is O;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen, methyl,        chloro, fluoro, methoxy, ethoxy and trifluoromethyl;    -   R² is selected from the group consisting of hydrogen, bromo and        methyl;    -   R³ is selected from the group consisting of hydrogen, methyl,        morpholinyl, morpholinomethyl, N-methylaminomethyl,        N,N-dimethylaminomethyl and cyano;    -   R⁸ is selected from the group consisting of methyl, ethyl and        cyclopropyl;    -   R⁹ is selected from the group consisting of hydrogen, methyl and        methoxy;    -   with the proviso that at least one of the following conditions        is fulfilled:    -   1) R² is bromo,    -   2) R³ is selected from the group consisting of morpholinyl and        cyano,    -   3) A⁴ or A⁵ or A⁶ is N.-   B9. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is C—R⁸; A² is C—R³; A³ is C—R⁹; Y is O;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen, methyl,        chloro, fluoro, methoxy, ethoxy and trifluoromethyl;    -   R² is selected from the group consisting of hydrogen, methyl    -   R³ is selected from the group consisting of hydrogen,        morpholinyl, morpholinomethyl, N,N-dimethylaminomethyl and        cyano;    -   R⁸ is selected from the group consisting of methyl, ethyl and        cyclopropyl;    -   R⁹ is selected from the group consisting of hydrogen, methyl and        methoxy;    -   with the proviso that at least one of the following conditions        is fulfilled:    -   1) R³ is selected from the group consisting of morpholinyl and        cyano    -   2) A⁴ or A⁵ or A⁶ is N.-   B10. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is C—CH₃; A² is C—R³; A³ is C—CH₃; Y is O;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—H;    -   R² is selected from the group consisting of hydrogen and methyl;    -   R³ is selected from the group consisting of hydrogen,        morpholinyl and cyano;    -   with the proviso that at least one of the following conditions        is fulfilled:    -   1) R³ is selected from the group consisting of morpholinyl and        cyano    -   2) A⁴ or A⁵ or A⁶ is N.-   B11. A compound selected from the group consisting of:-   3,9-dimethyl-2-morpholino-5-phenyl-7H-furo[3,2-g]chromen-7-one,-   3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,-   3,9-dimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,-   3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,-   3,6,9-trimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,-   3,9-dimethyl-5-(pyridin-2-yl)-7H-furo[3,2-g]chromen-7-one,-   5-(2-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,    and-   5-(4-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,    -   or a salt or solvate thereof.-   B12. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is C—R⁸; A² is C—R³; A³ is C—R⁹; Y is O;    -   one of A⁴ and A⁵ and A⁶ is N and the others are independently        selected from the group consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, halogen, (C₁-C₃)alkoxy and (C₁-C₃)haloalkyl;    -   R² is selected from the group consisting of hydrogen, halogen        and (C₁-C₃)alkyl;    -   R³ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, NR⁴R⁵, (C₁-C₃)alkyl-NR⁴R⁵ and cyano;    -   wherein R⁴ and R⁵ are independently selected from the group        consisting of hydrogen, (C₃-C₅)cycloalkyl,        (C₃-C₅)heterocycloalkyl, and (C₁-C₃)alkyl, or R⁴ and R⁵ together        with the nitrogen atom to which they are attached form a 5- to        7-membered heterocyclic ring optionally comprising in addition        to the aforementioned nitrogen atom a further heteroatom group        selected from the group consisting of O and NR⁶, wherein R⁶ is        selected from the group consisting of hydrogen, methyl, acetyl        and formyl;    -   R⁸ is selected from the group consisting of (C₁-C₄)alkyl,        (C₃-C₅)cycloalkyl and (C₃-C₅)heterocycloalkyl;    -   R⁹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl and (C₁-C₃)alkoxy.-   B13. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is C—R⁸; A² is C—R³; A³ is C—R⁹; Y is O;    -   one of A⁴ and A⁵ and A⁶ is N and the others are independently        selected from the group consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen, methyl,        chloro, fluoro, methoxy, ethoxy and trifluoromethyl;    -   R² is selected from the group consisting of hydrogen, bromo and        methyl;    -   R³ is selected from the group consisting of hydrogen, methyl,        morpholinyl, morpholinomethyl, N-methylaminomethyl,        N,N-dimethylaminomethyl and cyano;    -   R⁸ is selected from the group consisting of methyl, ethyl and        cyclopropyl;    -   R⁹ is selected from the group consisting of hydrogen, methyl and        methoxy.-   B14. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is C—R⁸; A² is C—R³; A³ is C—R⁹; Y is O;    -   one of A⁴ and A⁵ and A⁶ is N and the others are independently        selected from the group consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen, methyl,        chloro, fluoro, methoxy, ethoxy and trifluoromethyl;    -   R² is selected from the group consisting of hydrogen and methyl;    -   R³ is selected from the group consisting of hydrogen,        morpholinyl, morpholinomethyl, N,N-dimethylaminomethyl and        cyano;    -   R⁸ is selected from the group consisting of methyl, ethyl and        cyclopropyl;    -   R⁹ is selected from the group consisting of hydrogen, methyl and        methoxy.-   B15. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is C—CH₃; A² is C—H; A³ is C—CH₃; Y is O;    -   one of A⁴ and A⁵ and A⁶ is N and the others are independently        selected from the group consisting of N and C—H;    -   R² is selected from the group consisting of hydrogen and methyl.-   B16. A compound selected from the group consisting of:-   3,9-dimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,-   3,6,9-trimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,-   3,9-dimethyl-5-(pyridin-2-yl)-7H-furo[3,2-g]chromen-7-one,-   5-(2-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,    and-   5-(4-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,    -   or a salt or solvate thereof.-   B17. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is selected from the group consisting of N and C—R⁸;    -   A² is selected from the group consisting of N and C—R³;    -   A³ is selected from the group consisting of N and C—R⁹;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, halogen, (C₁-C₃)alkoxy and (C₁-C₃)haloalkyl;    -   R² is selected from the group consisting of hydrogen, halogen        and (C₁-C₃)alkyl;    -   R³ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, NR⁴R⁵, (C₁-C₃)alkyl-NR⁴R⁵ and cyano;    -   wherein R⁴ and R⁵ are independently selected from the group        consisting of hydrogen, (C₃-C₅)cycloalkyl,        (C₃-C₅)heterocycloalkyl, (C₁-C₃)alkyl, or R⁴ and R⁵ together        with the nitrogen atom to which they are attached form a 5- to        7-membered heterocyclic ring optionally comprising in addition        to the aforementioned nitrogen atom a further heteroatom group        selected from the group consisting of O and NR⁶, wherein R⁶ is        selected from the group consisting of hydrogen, methyl, acetyl        and formyl;    -   Y is selected from the group consisting of O and S, wherein if Y        is O, at least one of A¹, A² or A³ is N;

R⁸ is selected from the group consisting of (C₁-C₄)alkyl,(C₃-C₅)cycloalkyl and (C₃-C₅)heterocycloalkyl;

R⁹ is selected from the group consisting of hydrogen, (C₁-C₃)alkyl and(C₁-C₃)alkoxy;

-   -   with the proviso that        2-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one is excluded.

-   B18. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is selected from the group consisting of N and C—R⁸;    -   A² is selected from the group consisting of N and C—R³;    -   A³ is selected from the group consisting of N and C—R⁹;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen, methyl,        chloro, fluoro, methoxy, ethoxy and trifluoromethyl;    -   R² is selected from the group consisting of hydrogen, bromo and        methyl;    -   R³ is selected from the group consisting of hydrogen, methyl,        morpholinyl, morpholinomethyl, N-methylaminomethyl,        N,N-dimethylaminomethyl and cyano;    -   Y is selected from the group consisting of O and S, wherein if Y        is O, at least one of A¹, A² or A³ is N;    -   R⁸ is selected from the group consisting of methyl, ethyl and        cyclopropyl;    -   R⁹ is selected from the group consisting of hydrogen, methyl and        methoxy;    -   with the proviso that        2-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one is excluded.

-   B19. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   A¹ is selected from the group consisting of N and C—CH₃;    -   A² is selected from the group consisting of N and C—R³;    -   A³ is selected from the group consisting of N and C—CH₃;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—H;    -   R² is selected from the group consisting of hydrogen and methyl;    -   R³ is selected from the group consisting of hydrogen, methyl and        N-methylaminomethyl;    -   Y is selected from the group consisting of O and S, wherein if Y        is O, at least one of A¹, A² or A³ is N;    -   with the proviso that        2-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one is excluded.

-   B20. A compound selected from the group consisting of:

-   3-methyl-5-phenyl-7H-furo[2,3-b]pyrano[3,2-e]pyridin-7-one,

-   3,6-dimethyl-5-phenyl-7H-furo[2,3-b]pyrano[3,2-e]pyridin-7-one,

-   3,6,9-trimethyl-5-phenyl-7H-chromeno[6,7-d]isoxazol-7-one,

-   6,9-dimethyl-4-phenyl-2H-thieno[3,2-g]chromen-2-one,

-   2,4-dimethyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one,

-   4-methyl-2-((methylamino)methyl)-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one,

-   3,6,9-trimethyl-4-phenyl-2H-thieno[3,2-g]chromen-2-one,

-   4-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one,

-   2,4,7-trimethyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one, and

-   3,9-dimethyl-5-phenyl-7H-chromeno[6,7-d]isoxazol-7-one,    -   or a salt or solvate thereof.

-   B21. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is S;    -   A¹ is selected from the group consisting of N and C—R⁸;

A² is selected from the group consisting of N and C—R³;

-   -   A³ is selected from the group consisting of N and C—R⁹;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, halogen, (C₁-C₃)alkoxy and (C₁-C₃)haloalkyl;    -   R² is selected from the group consisting of hydrogen, halogen        and (C₁-C₃)alkyl;    -   R³ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, NR⁴R⁵, (C₁-C₃)alkyl-NR⁴R⁵ and cyano;    -   wherein R⁴ and R⁵ are independently selected from the group        consisting of hydrogen, (C₃-C₅)cycloalkyl,        (C₃-C₅)heterocycloalkyl, (C₁-C₃)alkyl, or R⁴ and R⁵ together        with the nitrogen atom to which they are attached form a 5- to        7-membered heterocyclic ring optionally comprising in addition        to the aforementioned nitrogen atom a further heteroatom group        selected from the group consisting of O and NR⁶, wherein R⁶ is        selected from the group consisting of hydrogen, methyl, acetyl        and formyl; R⁸ is selected from the group consisting of        (C₁-C₄)alkyl, (C₃-C₅)cycloalkyl and (C₃-C₅)heterocycloalkyl;

R⁹ is selected from the group consisting of hydrogen, (C₁-C₃)alkyl and(C₁-C₃)alkoxy.

-   B22. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is S;    -   A¹ is selected from the group consisting of N and C—R⁸;    -   A² is selected from the group consisting of N and C—R³;    -   A³ is selected from the group consisting of N and C—R⁹;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen, methyl,        chloro, fluoro, methoxy, ethoxy and trifluoromethyl;    -   R² is selected from the group consisting of hydrogen, bromo and        methyl;    -   R³ is selected from the group consisting of hydrogen, methyl,        morpholinyl, morpholinomethyl, N-methylaminomethyl,        N,N-dimethylaminomethyl and cyano;    -   R⁸ is selected from the group consisting of methyl, ethyl and        cyclopropyl;    -   R⁹ is selected from the group consisting of hydrogen, methyl and        methoxy.-   B23. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is S;    -   A¹ is selected from the group consisting of N and C—CH₃;    -   A² is selected from the group consisting of N and C—R³    -   A³ is selected from the group consisting of N and C—CH₃;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—H;    -   R² is selected from the group consisting of hydrogen and methyl;    -   R³ is selected from the group consisting of hydrogen, methyl and        N-methylaminomethyl.-   B24. A compound selected from the group consisting of:-   6,9-dimethyl-4-phenyl-2H-thieno[3,2-g]chromen-2-one, and-   3,6,9-trimethyl-4-phenyl-2H-thieno[3,2-g]chromen-2-one,    -   or a salt or solvate thereof.-   B25. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is O;    -   A¹ is selected from the group consisting of N and C—R⁸;    -   A² is selected from the group consisting of N and C—R³;    -   A³ is selected from the group consisting of N and C—R⁹;    -   wherein at least one of A¹, A² or A³ is N;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, halogen, (C₁-C₃)alkoxy and (C₁-C₃)haloalkyl;    -   R² is selected from the group consisting of hydrogen, halogen        and (C₁-C₃)alkyl;    -   R³ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, NR⁴R⁵, (C₁-C₃)alkyl-NR⁴R⁵ and cyano;    -   wherein R⁴ and R⁵ are independently selected from the group        consisting of hydrogen, (C₃-C₅)cycloalkyl,        (C₃-C₅)heterocycloalkyl and (C₁-C₃)alkyl, or R⁴ and R⁵ together        with the nitrogen atom to which they are attached form a 5- to        7-membered heterocyclic ring optionally comprising in addition        to the aforementioned nitrogen atom a further heteroatom group        selected from the group consisting of O and NR⁶, wherein R⁶ is        selected from the group consisting of hydrogen, methyl, acetyl        and formyl;    -   R⁸ is selected from the group consisting of (C₁-C₄)alkyl,        (C₃-C₅)cycloalkyl and (C₃-C₅)heterocycloalkyl;    -   R⁹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl and (C₁-C₃)alkoxy: with the proviso that        2-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one is excluded.-   B26. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is O;    -   A¹ is selected from the group consisting of N and C—R⁸;    -   A² is selected from the group consisting of N and C—R³;    -   A³ is selected from the group consisting of N and C—R⁹;    -   wherein at least one of A¹, A² or A³ is N;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen, methyl,        chloro, fluoro, methoxy, ethoxy and trifluoromethyl;    -   R² is selected from the group consisting of hydrogen, bromo and        methyl;    -   R³ is selected from the group consisting of hydrogen, methyl,        morpholinyl, morpholinomethyl, N-methylaminomethyl,        N,N-dimethylaminomethyl and cyano;    -   R⁸ is selected from the group consisting of methyl, ethyl and        cyclopropyl;    -   R⁹ is selected from the group consisting of hydrogen, methyl and        methoxy; with the proviso that        2-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one is excluded.-   B27. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is O;    -   A¹ is selected from the group consisting of N and C—CH₃;    -   A² is selected from the group consisting of N and C—R³    -   A³ is selected from the group consisting of N and C—CH₃;    -   wherein at least one of A¹, A² or A³ is N;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—H;    -   R² is selected from the group consisting of hydrogen and methyl;    -   R³ is selected from the group consisting of hydrogen, methyl and        N-methylaminomethyl;    -   with the proviso that        2-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one is excluded.-   B28. A compound selected from the group consisting of:-   3-methyl-5-phenyl-7H-furo[2,3-b]pyrano[3,2-e]pyridin-7-one,-   3,6-dimethyl-5-phenyl-7H-furo[2,3-b]pyrano[3,2-e]pyridin-7-one,-   3,6,9-trimethyl-5-phenyl-7H-chromeno[6,7-d]isoxazol-7-one,-   2,4-dimethyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one,-   4-methyl-2-((methylamino)methyl)-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one,-   4-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one,-   2,4,7-trimethyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one, and-   3,9-dimethyl-5-phenyl-7H-chromeno[6,7-d]isoxazol-7-one,    -   or a salt or solvate thereof.-   B29. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is O; A³ is N;    -   A¹ is selected from the group consisting of N and C—R⁸;    -   A² is selected from the group consisting of N and C—R³;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, halogen, (C₁-C₃)alkoxy and (C₁-C₃)haloalkyl;    -   R² is selected from the group consisting of hydrogen, halogen        and (C₁-C₃)alkyl;    -   R³ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, NR⁴R⁵, (C₁-C₃)alkyl-NR⁴R⁵ and cyano;    -   wherein R⁴ and R⁵ are independently selected from the group        consisting of hydrogen, (C₃-C₅)cycloalkyl,        (C₃-C₅)heterocycloalkyl, (C₁-C₃)alkyl, or R⁴ and R⁵ together        with the nitrogen atom to which they are attached form a 5- to        7-membered heterocyclic ring optionally comprising in addition        to the aforementioned nitrogen atom a further heteroatom group        selected from the group consisting of O and NR⁶, wherein R⁶ is        selected from the group consisting of hydrogen, methyl, acetyl        and formyl;    -   R⁸ is selected from the group consisting of (C₁-C₄)alkyl,        (C₃-C₅)cycloalkyl and (C₃-C₅)heterocycloalkyl.-   B30. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is O; A³ is N;    -   A¹ is selected from the group consisting of N and C—R⁸;    -   A² is selected from the group consisting of N and C—R³;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen, methyl,        chloro, fluoro, methoxy, ethoxy and trifluoromethyl;    -   R² is selected from the group consisting of hydrogen, bromo and        methyl;    -   R³ is selected from the group consisting of hydrogen, methyl,        morpholinyl, morpholinomethyl, N-methylaminomethyl,        N,N-dimethylaminomethyl and cyano;    -   R⁸ is selected from the group consisting of methyl, ethyl and        cyclopropyl.-   B31. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is O; A³ is N;    -   A¹ is selected from the group consisting of N and C—CH₃;    -   A² is selected from the group consisting of N and C—R³;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—H;    -   R² is selected from the group consisting of hydrogen and methyl;    -   R³ is selected from the group consisting of hydrogen, methyl and        N-methylaminomethyl.-   B32. A compound selected from the group consisting of:-   3-methyl-5-phenyl-7H-furo[2,3-b]pyrano[3,2-e]pyridin-7-one, and-   3,6-dimethyl-5-phenyl-7H-furo[2,3-b]pyrano[3,2-e]pyridin-7-one.-   B33. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is O; A¹ is N; A² is C—R³    -   A³ is selected from the group consisting of N and C—R⁹;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of R¹ is selected from        the group consisting of hydrogen, (C₁-C₃)alkyl, halogen,        (C₁-C₃)alkoxy and (C₁-C₃)haloalkyl;    -   R² is selected from the group consisting of hydrogen, halogen        and (C₁-C₃)alkyl;    -   R³ is selected from the group consisting of R³ is selected from        the group consisting of hydrogen, (C₁-C₃)alkyl, NR⁴R⁵,        (C₁-C₃)alkyl-NR⁴R⁵ and cyano;    -   wherein R⁴ and R⁵ are independently selected from the group        consisting of hydrogen, (C₃-C₅)cycloalkyl,        (C₃-C₅)heterocycloalkyl and (C₁-C₃)alkyl, or R⁴ and R⁵ together        with the nitrogen atom to which they are attached form a 5- to        7-membered heterocyclic ring optionally comprising in addition        to the aforementioned nitrogen atom a further heteroatom group        selected from the group consisting of O and NR⁶, wherein R⁶ is        selected from the group consisting of hydrogen, methyl, acetyl        and formyl;    -   R⁹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl and (C₁-C₃)alkoxy;    -   with the proviso that        2-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one is excluded.-   B34. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is O; A¹ is N; A² is C—R³    -   A³ is selected from the group consisting of N and C—R⁹;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen, methyl,        chloro, fluoro, methoxy, ethoxy and trifluoromethyl;    -   R² is selected from the group consisting of hydrogen, bromo and        methyl;    -   R³ is selected from the group consisting of R³ is selected from        the group consisting of hydrogen, methyl, morpholinyl,        morpholinomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl        and cyano;    -   R⁹ is selected from the group consisting of hydrogen, methyl and        methoxy;    -   with the proviso that        2-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one is excluded.-   B35. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is O; A¹ is N; A² is C—R³    -   A³ is selected from the group consisting of N and C—CH₃;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—H;    -   R² is selected from the group consisting of hydrogen and methyl;    -   R³ is selected from the group consisting of R³ is selected from        the group consisting of hydrogen, methyl and        N-methylaminomethyl.-   B36. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is O; A¹ is N; A² is C—R³; A³ is C—CH₃; A⁴ and A⁵ and A⁶ are        C—H;    -   R² is selected from the group consisting of hydrogen and methyl;    -   R³ is selected from the group consisting of R³ is selected from        the group consisting of hydrogen, methyl and        N-methylaminomethyl.-   B37. A compound selected from the group consisting of:-   2,4-dimethyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one,-   4-methyl-2-((methylamino)methyl)-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one,-   4-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one, and-   2,4,7-trimethyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one,    -   or a salt or solvate thereof.-   B38. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is O;    -   A¹ is C—R⁸;    -   A² is N;    -   A³ is selected from the group consisting of N and C—R⁹;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl, halogen, (C₁-C₃)alkoxy and (C₁-C₃)haloalkyl;    -   R² is selected from the group consisting of hydrogen, halogen        and (C₁-C₃)alkyl;    -   R⁸ is selected from the group consisting of (C₁-C₄)alkyl,        (C₃-C₅)cycloalkyl and (C₃-C₅)heterocycloalkyl;    -   R⁹ is selected from the group consisting of hydrogen,        (C₁-C₃)alkyl and (C₁-C₃)alkoxy.-   B39. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is O; A¹ is C—R⁸; A² is N;    -   A³ is selected from the group consisting of N and C—R⁹;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—R¹;    -   R¹ is selected from the group consisting of hydrogen, methyl,        chloro, fluoro, methoxy, ethoxy and trifluoromethyl;    -   R² is selected from the group consisting of hydrogen, bromo and        methyl;    -   R⁸ is selected from the group consisting of methyl, ethyl and        cyclopropyl;    -   R⁹ is selected from the group consisting of hydrogen, methyl and        methoxy.-   B40. A compound of the general formula (II) or a salt or solvate    thereof, wherein    -   Y is O; A¹ is C—CH₃; A² is N;    -   A³ is selected from the group consisting of N and C—CH₃;    -   A⁴ and A⁵ and A⁶ are independently selected from the group        consisting of N and C—H;    -   R² is selected from the group consisting of hydrogen and methyl.-   B41. A compound selected from the group consisting of:    -   3,6,9-trimethyl-5-phenyl-7H-chromeno[6,7-d]isoxazol-7-one, and        3,9-dimethyl-5-phenyl-7H-chromeno[6,7-d]isoxazol-7-one, or a        salt or solvate thereof.

In particular embodiments of the present invention A⁶ is C—R¹, moreparticularly C—H.

In other particular embodiments of the present invention A⁶ is N.

More particular embodiments of the present invention are the respectivespecific compounds of below Tables 1 and/or 2 which are encompassed byeach respective of the aforementioned enumerated embodiments, even moreparticularly those having an IC₅₀ marked with “++” or “+++”, yet evenmore particularly those having an IC₅₀ marked with “+++”.

To keep the definitions as short as possible, the term “alkyl” is to beunderstood to encompass in certain embodiments alkyl, alkenyl andalkynyl. It is apparent to the skilled person that “C₁-alkenyl” and“C₁-alkynyl” are not meant to be included.

In the context of the present invention, a (C₁-C₄)alkyl group, if notstated otherwise, particularly denotes a linear or branched(C₁-C₄)alkyl, more particularly selected from the group consisting of—CH₃, —C₂H₅, —CH═CH₂, —C≡CH, —C₃H₇, —CH(CH₃)₂, —CH₂—CH═CH₂, —C(CH₃)═CH₂,—CH═CH—CH₃, —C≡C—CH₃, —CH₂—C≡CH, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅,and —C(CH₃)₃, even more particularly selected from the group consistingof —CH₃, —C₂H₅, —(CH₂)₂CH₃, —CH(CH₃)₂, —(CH₂)₃CH₃, —CH₂—CH(CH₃)₂,—CH(CH₃)—C₂H, and —C(CH₃)₃. The aforementioned alkyl groups mayindependently be substituted by one or more (C1-C3)alkoxy groups,particularly by one (C1-C3)alkoxy group, wherein particularly said(C1-C₃)alkoxy is unsubstituted.

In the context of the present invention, a (C₁-C₃)alkyl group, if notstated otherwise, particularly denotes a linear or branched(C₁-C₃)alkyl, more particularly selected from the group consisting of—CH₃, —C₂H₅, —(CH₂)₂CH₃, —CH(CH₃)₂, —(CH₂)₃CH₃, —CH₂—CH(CH₃)₂,—CH(CH₃)—C₂H₅, and —C(CH₃)₃. The aforementioend alkyl groups mayindependently be substituted by one or more (C₁-C₃)alkoxy groups,particularly by one (C₁-C₃)alkoxy group, wherein particularly said(C₁-C₃)alkoxy is unsubstituted.

In context of the present invention, a (C₃-C₅)cycloalkyl group denotes anon-aromatic ring system containing three to five carbon atoms,particularly cyclopropane, cyclobutane, cyclopentane and cyclopentene.The aforementioned cycloalkyl groups may independently be substituted byone or more (C₁-C₃)alkoxy and/or (C₁-C₃)alkyl groups, particularly byone (C₁-C₃)alkoxy or (C₁-C₃)alkyl group, wherein particularly said(C₁-C₃)alkoxy and (C₁-C₃)alkyl is unsubstituted.

In context of the present invention, a (C₃-C₅)heterocycloalkyl groupdenotes a non-aromatic ring system containing three to five carbonatoms, wherein one or more, particularly one, of the carbon atoms in thering are replaced by a heteroatom group selected from the groupcomprising O, S, SO, SO₂, N, and NR″, particularly selected from thegroup comprising O, SO₂ and NR″, wherein R″ is independently selectedfrom the group consisting of hydrogen, (C₁-C₄)alkyl, formyl, and acetyl.Particularly said (C₃-C₅)heterocycloalkyl group is selected from thegroup consisting of -oxetan-2-yl, -oxetan-3-yl, -tetrahydrofuran-2-yl,-tetrahydrofuran-3-yl, -aziridin-2-yl, -azetidin-2-yl, -azetidin-3-yl,-pyrrolidin-2-yl, -pyrrolidin-3-yl, 1,1-dioxidotetrahydrothiophen-3-yl,1,1-dioxidothietan-3-yl, more particularly selected from the groupconsisting of -tetrahydrofuran-2-yl, -tetrahydrofuran-3-yl,-aziridin-2-yl, -pyrrolidin-2-yl, and -pyrrolidin-3-yl, whereinindependently -aziridin-2-yl, -azetidin-2-yl, -azetidin-3-yl,-pyrrolidin-2-yl, -pyrrolidin-3-yl, is on their respective nitrogen atomsubstituted with a residue R″ as detailed above. The aforementionedheterocycloalkyl groups may independently be substituted by one or more(C₁-C₃)alkoxy and/or (C₁-C₃)alkyl groups, particularly by one(C₁-C₃)alkoxy or (C₁-C₃)alkyl group, wherein particularly said(C₁-C₃)alkoxy and (C₁-C₃)alkyl is unsubstituted.

A (C₁-C₃)alkoxy group denotes an O—(C₁-C₃)alkyl group, wherein therespective alkyl part is as defined above; in particular embodiments ofthe present invention the (C₁-C₃)alkoxy group is selected from the groupcomprising methoxy, ethoxy, and isopropoxy.

A (C₁-C₃)haloalkyl group denotes a (C₁-C₃)alkyl group as defined abovesubstituted by one or more halogen atoms, particularly substituted byone to five halogen atoms. More particularly the (C1-C3)haloalkyl groupis selected from the group consisting of —C(R¹⁰)₃, —CR¹⁰(R^(10′))₂,—CR¹⁰(R^(10′))R^(10″), —C₂(R¹⁰), —CH₂—C(R¹⁰)₃,—C(R^(10′))₂—CH(R^(10′))₂, —CH₂—CR¹⁰(R^(10′))₂, —CH₂—CR¹⁰(R^(10′))R¹⁰,—C₃(R¹⁰)₇, or —C₂H₄—C(R¹⁰)₃, wherein R¹⁰, R^(10′), R^(10″) independentlyrepresent F, Cl, Br or I, particularly F; more particularly,(C—C₃)haloalkyl is CF₃.

In particular embodiments of the present invention a halo or halogengroup denotes fluoro, chloro, bromo, or iodo; particularly bromo, chloroor fluoro.

Constituents which are optionally substituted as stated herein may besubstituted, unless otherwise noted, at any chemically possibleposition.

According to expert's knowledge the compounds of the invention as wellas their salts may contain, e.g. when isolated in crystalline form,varying amounts of solvents. Included within the scope of the inventionare therefore all solvates and in particular all hydrates of thecompounds of the present invention as well as all solvates and inparticular all hydrates of the salts of the compounds of the presentinvention. Particular solvates or hydrates are stoichiometric orsubstoichiometric solvates or hydrates comprising 0.5, 1 or 2 solvate orwater molecules per molecule of compound of the present invention.

In the method for producing a compound according the present invention,

wherein W is

or wherein

is used for transition metal mediated acylation at the position markedwith an asterisk in formula II′, R⁸ is formed from the aforementionedgroup W² upon the transition metal mediated coupling at the positionmarked with an asterisk in formula II′, wherein a hydrogen atom is addedto the carbon atom of W² being part of the double bond, wherein theresulting R⁸ can in this case be selected from the group consisting ofmethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and isobutyl.

To describe a certain aspect of the method for producing a compoundaccording to the present invention in further detail, transition metalmediated alkylation at the position marked with an asterisk in formulaII′ means in particular that a carbon-carbon bond is formed between thecarbon atom at the position marked with an asterisk in formula II′ (thusreplacing the bromine atom) and the carbon atom of group W being part ofthe double bond (either to carbon or oxygen) and allowing for anexocyclic cyclization (resulting in the formation of a 5-membered ring).

To describe a certain aspect of the present invention in further detail,in the method for producing a compound according to the presentinvention wherein W is hydrogen (i.e. the group —Y—W is —Y—H), thetransition metal mediated acylation at the position marked with anasterisk in formula II′ as described above is accomplished first (thusreplacing the bromine atom with a group —CO—R⁸), followed by cyclizationusing hydroxylamine. In particular embodiments of said method wherein Wis hydrogen, said cyclization using hydroxylamine is characterized by astep of converting the carbonyl group of the aforementioned group —CO—R⁸into an oxim using hydroxylamine, followed by a step of converting thehydroxy functionality of said oxim into a suitable leaving group (e.g.by acylation with Ac₂O), followed by intramolecular cyclization byheating either neat or under basic conditions (e.g. in the presence ofK₂CO₃ or pyridine); a possible representation is found in Scheme 5,steps SP-5A and SP-5C.

In particular embodiments of the method for producing a compoundaccording to the present invention, wherein W is

said transition metal mediated intramolecular alkylation at the positionmarked with an asterisk in the formula II′ is accomplished by using aPalladium-based catalyst, more particularly Pd(OAc)₂, particularly in apolar non-protic solvent, more particularly in DMF, particularly at atemperature from 60 to 130° C., more particularly at about 80° C., evenmore particularly in DMF at about 80° C.

In other particular embodiments of the method for producing a compoundaccording to the present invention, wherein W is

said transition metal mediated intramolecular alkylation at the positionmarked with an asterisk in the formula II′ is accomplished by using amixture of a Ni(II) and a Cr(II) salt, more particularly a mixture ofnickel(II) chloride and chromium(II) chloride, particularly in a polarnon-protic solvent, more particularly in DMF, particularly at atemperature from 100 to 150° C., more particularly at a temperature from120 to 140° C., even more particularly in DMF at a temperature from 120to 140° C.

In yet another particular embodiment, the method for producing acompound according to the present invention, wherein W is hydrogen, saidtransition metal mediated acylation at the position marked with anasterisk in the formula II′ is accomplished by using a Palladium-basedcatalyst, more particularly PdCl₂(PPh₃)₂, and1-ethoxyvinyl-tri-n-butyltin, particularly in a polar non-proticsolvent, more particularly DMF, particularly at temperatures from 120 to180° C., more particularly at about 160° C., even more particularly inDMF at about 160° C., yet even more particularly under microwaveirradiation.

As used herein the terms disease, indication and medical condition areused interchangeably.

A further embodiment of the present invention is a compound of thepresent invention for use as a medicament. A further embodiment of thepresent invention is the use of a compound of the present invention forthe manufacture of a medicament. A further embodiment of the presentinvention is a method of treatment, said method comprising administeringa therapeutically effective amount of a compound of the presentinvention to a subject in need thereof.

It is to be understood that the embodiments of the present inventionrelating to a compound of the present invention, in particular for usein the treatment of disease or a medical condition, dosage form,application route, etc, as detailed herein, likewise relate to the useof a compound of the present invention for the manufacture of amedicament for use in the treatment of said diseases or medicalconditions, as well as the methods of treating said diseases or medicalconditions comprising administering a therapeutically effective amountof a compound of the present invention to a subject in need thereof.

In a particular embodiment, the present invention relates to a compoundof the present invention for use in the treatment of a disease ormedical condition in which the inhibition of the voltage-gated potassiumchannel Kv1.3 is beneficial, particularly for a disease or medicalcondition selected from the group consisting of psoriasis, psoriatricarthritis, autoimmune thyroiditis, Hashimoto's disease, Grave's disease,rheumatoid arthritis, vitiligo, Crohn's disease, ulcerative colitis,inflammatory bowel disease, ankylosing spondylitis (Morbus Bechterew),periodontal disease, diabetes type I, multiple sclerosis, systemic lupuserythematosus, anti-glomerular basement membrane glomerulonephritis,rapidly progressive glomerulonephritis, advanced chronic renal failure,chronic kidney disease, renal fibrosis, uveitis, Pars planitis, asthma,Pemphigus foliaceus, inclusion body myositis, dermatomyositis,scleroderma, Behcet disease, atopic dermatitis, allergic and irritantcontact dermatitis, Lichen planus, Sjögren's syndrome,Graft-versus-Host-Reaction, Host-versus-Graft-Reaction, transplantrejection, end-stage renal disease, vascularized compositeallotransplantation rejection, alopecia areata, inflammatory boneresorption disease, anti-neutrophil cytoplasmic autoantibody-associatedvasculitis, osteoarthritis, diseases associated with intimalhyperplasia, breast cancer, leukemia, chronic lymphocytic leukemia,human lung adenocarcinoma, cutaneous T-cell lymphoma, osteosarcoma,neuroblastoma, ovarian cancer and melanoma, neuroinflammatory disorders,neurodegeneration, HIV-1-associated neurocognitive disorders (HAND),microglia-induced oxidative stress in Alzheimer's disease, obesity, andinsulin resistance, restenosis/neointimal hyperplasia, atherosclerosis(arteriosclerotic vascular disease or ASVD), acute coronary syndrome,acute ischemic stroke, hypertension.

In a further particular embodiment, the present invention relates to acompound of the present invention for use in the treatment of a diseaseor medical condition in which the inhibition of the voltage-gatedpotassium channel Kv1.3 is beneficial, particularly for a disease ormedical condition selected from the group consisting of psoriasis,psoriatic arthritis, autoimmune thyroiditis, Hashimoto's disease,Grave's disease, rheumatoid arthritis, vitiligo, Crohn's disease,inflammatory bowel disease, ulcerative colitis, diabetes type I,multiple sclerosis, systemic lupus erythematosus, anti-glomerularbasement membrane glomerulonephritis, rapidly progressiveglomerulonephritis, advanced chronic renal failure, chronic kidneydisease, renal fibrosis, uveitis, Pars planitis, asthma, Pemphigusfoliaceus, inclusion body myositis, dermatomyositis, scleroderma,allergic and irritant contact dermatitis, Sjögren's syndrome,Graft-versus-Host-Reaction, transplant rejection, end-stage renaldisease, vascularized composite allotransplantation rejection, alopeciaareata, inflammatory bone resorption disease, anti-neutrophilcytoplasmic autoantibody-associated vasculitis, diseases associated withintimal hyperplasia, breast cancer, leukemia, human lung adenocarcinoma,chronic lymphocytic leukemia, osteosarcoma, melanoma, neuroinflammatorydisorders, neurodegeneration, HIV-1-associated neurocognitive disorders(HAND), microglia-induced oxidative stress in Alzheimer's disease,obesity, and insulin resistance, restenosis/neointimal hyperplasia,atherosclerosis (arteriosclerotic vascular disease or ASVD), acutecoronary syndrome, acute ischemic stroke, hypertension.

In a further particular embodiment, the present invention relates to acompound of the present invention for use in the treatment of a diseaseor medical condition in which inhibition of Kv1.3 results in a (partial)immunosuppression, more particularly for an autoimmune disease orchronic inflammatory disease selected from the group consisting ofpsoriasis, psoriatric arthritis, autoimmune thyroiditis, Hashimoto'sdisease, Grave's disease, rheumatoid arthritis, vitiligo, Crohn'sdisease, ulcerative colitis, inflammatory bowel disease, ankylosingspondylitis, periodontal disease, diabetes type I, multiple sclerosis,systemic lupus erythematosus, anti-glomerular basement membraneglomerulonephritis, rapidly progressive glomerulonephritis, chronickidney disease, uveitis, Pars planitis, asthma, Pemphigus foliaceus,inclusion body myositis, dermatomyositis, scleroderma, Behcet disease,atopic dermatitis, allergic and irritant contact dermatitis, Lichenplanus, Sjögren's syndrome, Graft-versus-Host-Reaction,Host-versus-Graft-Reaction, transplant rejection, end-stage renaldisease, vascularized composite allotransplantation rejection, alopeciaareata, inflammatory bone resorption disease, anti-neutrophilcytoplasmic autoantibody-associated vasculitis, osteoarthritis, diseasesassociated with intimal hyperplasia, restenosis/neointimal hyperplasia,neuroinflammatory disorders, neurodegeneration, atherosclerosis(arteriosclerotic vascular disease or ASVD), hypertension.

In yet a further particular embodiment, the present invention relates toa compound of the present invention for use in the treatment of adisease or medical condition selected from the group consisting ofpsoriatric arthritis, autoimmune thyroiditis, Hashimoto's disease,Grave's disease, rheumatoid arthritis, Crohn's disease, ulcerativecolitis, inflammatory bowel disease, ankylosing spondylitis, periodontaldisease, diabetes type I, multiple sclerosis, systemic lupuserythematosus, anti-glomerular basement membrane glomerulonephritis,rapidly progressive glomerulonephritis, chronic kidney disease, uveitis,Pars planitis, asthma, Pemphigus foliaceus, inclusion body myositis,dermatomyositis, scleroderma, Behcet disease, atopic dermatitis,allergic and irritant contact dermatitis, Lichen planus, Sjögren'ssyndrome, Graft-versus-Host-Reaction, Host-versus-Graft-Reaction,transplant rejection, end-stage renal disease, vascularized compositeallotransplantation rejection, alopecia areata, inflammatory boneresorption disease, anti-neutrophil cytoplasmic autoantibody-associatedvasculitis, osteoarthritis, diseases associated with intimalhyperplasia, restenosis/neointimal hyperplasia, neuroinflammatorydisorders, neurodegeneration, atherosclerosis (arteriosclerotic vasculardisease or ASVD), hypertension.

In yet a further particular embodiment, the present invention relates toa compound of the present invention for use in the treatment of adisease or medical condition selected from the group consisting ofpsoriasis, rheumatoid arthritis, diabetes type I, multiple sclerosis,anti-glomerular basement membrane glomerulonephritis, rapidlyprogressive glomerulonephritis, advanced chronic renal failure, chronickidney disease, renal fibrosis, allergic and irritant contactdermatitis, transplant rejection, asthma, end-stage renal disease,vascularized composite allotransplantation rejection, alopecia areata,inflammatory bone resorption disease, human lung adenocarcinoma,melanoma, neuroinflammatory disorders, neurodegeneration, obesity, andinsulin resistance, restenosis/neointimal hyperplasia, atherosclerosis(arteriosclerotic vascular disease or ASVD), acute coronary syndrome.

In yet a further particular embodiment, the present invention relates toa compound of the present invention for use in the treatment of adisease or medical condition selected from the group consisting ofrheumatoid arthritis, diabetes type I, multiple sclerosis,anti-glomerular basement membrane glomerulonephritis, rapidlyprogressive glomerulonephritis, advanced chronic renal failure, chronickidney disease, renal fibrosis, allergic and irritant contactdermatitis, transplant rejection, asthma, end-stage renal disease,vascularized composite allotransplantation rejection, alopecia areata,inflammatory bone resorption disease, human lung adenocarcinoma,melanoma, neuroinflammatory disorders, neurodegeneration, obesity, andinsulin resistance, restenosis/neointimal hyperplasia, atherosclerosis(arteriosclerotic vascular disease or ASVD), acute coronary syndrome.

In yet a further particular embodiment, the present invention relates toa compound of the present invention for use in the treatment of adisease or medical condition selected from the group consisting ofpsoriasis, atopic dermatitis, allergic and irritant contact dermatitis,rheumatoid arthritis, and uveitis, multiple sclerosis.

In yet a further particular embodiment, the present invention relates toa compound of the present invention for use in the treatment of adisease or medical condition selected from the group consisting ofatopic dermatitis, allergic and irritant contact dermatitis, rheumatoidarthritis, and uveitis, multiple sclerosis.

In another particular embodiment, the present invention relates to acompound of the present invention for use in the treatment of a diseaseor medical condition in which inhibition of Kv1.3 results in anantiproliferative response, in particular a disease or medical conditionselected from the group consisting of breast cancer, ovarian cancer,leukemia, chronic lymphocytic leukemia, osteosarcoma, neuroblastoma,human lung adenocarcinoma, melanoma, restenosis, neointimal hyperplasia.

In another particular embodiment, the present invention relates to acompound of the present invention for use in the treatment of a diseaseor medical condition in which inhibition of Kv1.3 results in aneuroprotective response, in particular for the treatment ofneurodegeneration.

In another particular embodiment, the present invention relates to acompound of the present invention for use in the treatment of a diseaseor medical condition in which inhibition of Kv1.3 results in amodulation of cellular metabolism, in particular a disease or medicalcondition selected from the group consisting of obesity and insulinresistance.

In another particular embodiment, the present invention relates to acompound of the present invention for use in the treatment of a diseaseor medical condition treatable by inhibition of Kv1.3^(high) phenotypecells, particularly Kv1.3^(high) phenotype immune system cells, moreparticularly class-switched memory B-cells and/or effector memoryT-cells of the Kv1.3^(high) phenotype, even more particularly T-celldriven autoimmune disorders and chronic inflammation conditions, inparticular selected from the group consisting of psoriatic arthritis,Type 1 diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis,asthma, anti-glomerular basement membrane glomerulonephritis, acutecoronary syndrome. In this context, Kv1.3^(high) phenotype cells arecells wherein Kv1.3 expression numbers range from 750 to 2900,particularly 950 to 2900 Kv1.3 channels per cell, which can bedetermined either by immunohistochemical staining or patch-clampanalysis well known to the skilled person, and for example described inWulff et al., J. Clin. Invest. 2003, 111, 1703; Rus et al., PNAS 2005,102, 11094.

In the context of the present invention, whether the Kv1.3 expression incells of a subject is high as defined herein, can particularly bedetermined by

-   -   1) obtaining a sample from said subject,    -   2) optionally isolating cells wherein Kv1.3 expression is to be        determined from said sample,    -   3) optionally culturing said cells in a suitable medium,    -   4) determining the Kv1.3 expression in said cells,        wherein in particular cases    -   said sample is a fluid sample, particularly a synovial or        cerebrospinal fluid sample, leukapheresis sample, or peripheral        blood sample, e.g. from a subject suspected of suffering from        rheumatoid arthritis, or a tissue sample, particularly a sample        from the affected tissue, such as a psoriatic lesion, synovial        tissue or brain infiltrate, from said subject;    -   said cells wherein Kv1.3 expression is to be determined are        particularly lymphocytes, B-cells, or T-cells, such as T_(EM)        cells; CD4⁺ T-cells or CD8⁺ T-cells;    -   said cells wherein Kv1.3 expression is to be determined are        isolated by techniques known in the art, particularly density        gradient centrifugation and FACS (fluorescence activated cell        sorting), wherein in particular such isolation is used in the        case of fluid samples;    -   said suitable medium is known in the art, e.g. Dulbecco's media,        such as Iscove's modified Dulbecco's medium, which may be        supplemented with the necessary additives, such as antibiotics;    -   in the case of tissue samples, the isolation and culturing may        in certain cases be replaced by a step of sample preparation,        e.g. paraffin preparation;    -   the Kv1.3 expression in said cells is determined via art-known        techniques, particularly by patch-clamp, such as the patch-clamp        techniques referenced herein, or by subjecting said cells to        immunohistochemical staining and determining Kv1.3 expression by        fluorescence microscopy, such as described in the literature        references included herein, wherein the corresponding Kv1.3        expression in said cells may be calculated from the results        obtained by the aforementioned techniques via art-known methods,        such as described in the literature references included herein;        examples of such methods are described in e.g. PNAS 2006, 103,        17414; J. Clin. Invest. 2003, 111, 1703; J. Invest. Dermatol.        2011, 131, 118; PNAS 2005, 102, 11094.

The present invention further relates to pharmaceutical compositions,kits and kits-of-parts comprising a compound of the present invention.

The present invention further relates to the use of a compound of thepresent invention for the production of pharmaceutical compositions, andto pharmaceutical compositions comprising a compound of the presentinvention, which in further particular embodiments are employed for thetreatment and/or prophylaxis of the diseases and/or medical conditionsas disclosed herein.

In particular, the pharmaceutical compositions as described hereincomprise a compound of the present invention and a pharmaceuticallyacceptable carrier or diluent.

Additionally, the invention relates to an article of manufacture, whichcomprises packaging material and a pharmaceutical agent contained withinsaid packaging material, wherein the pharmaceutical agent istherapeutically effective against the medical conditions as describedherein, and wherein the packaging material comprises a label or packageinsert which indicates that the pharmaceutical agent is useful forpreventing or treating the medical conditions disclosed herein, andwherein said pharmaceutical agent comprises one or more compounds of thepresent invention. The packaging material, label and package insertotherwise parallel or resemble what is generally regarded as standardpackaging material, labels and package inserts for pharmaceuticalshaving related utilities.

The pharmaceutical compositions of the present invention are prepared byprocesses which are known per se and familiar to the person skilled inthe art. As pharmaceuticals, the compounds of the present invention canbe either employed as such, or particularly in combination with suitablepharmaceutical auxiliaries and/or excipients, e.g. in the form oftablets, coated tablets, capsules, caplets, suppositories, patches (e.g.as TTS), emulsions, suspensions, gels or solutions, the active compoundcontent for example being from 0.1-99% or from 0.1-95% and where, by theappropriate choice of the auxiliaries and/or excipients, apharmaceutical administration form (e.g. a delayed release form or anenteric form) suited to the active compound and/or to the desired onsetof action to be achieved.

In particular embodiments, administration routes are selected from thegroup consisting of intravenous, oral, intramuscular, intraocular,topical, and enteral.

A customary dose of the compounds of the present invention in the caseof systemic therapy (p.o.) is usually between 0.3 and 30 mg/kg per day,or between 0.3 and 100 mg/kg per day, (i.v.) is usually between 0.3 and30 mg/kg/h. The choice of the optimal dosage regime and duration ofmedication, particularly the optimal dose and manner of administrationof the active compounds necessary in each case can be determined by aperson skilled in the art on the basis of his/her expert knowledge.

The person skilled in the art is familiar with auxiliaries, vehicles,excipients, diluents, carriers or adjuvants which are suitable for thedesired pharmaceutical formulations, preparations or compositions onaccount of his/her expert knowledge. In addition to solvents, gelformers, ointment bases and other active compound excipients, forexample antioxidants, dispersants, emulsifiers, preservatives,solubilizers, colorants, complexing agents or permeation promoters, canbe used in the pharmaceutical compositions of the present invention.

Depending upon the particular disease and/or medical condition to betreated or prevented, additional therapeutic active agents, which arenormally administered to treat or prevent that disease, may optionallybe coadministered with the compounds according to the present invention.As used herein, additional therapeutic agents that are normallyadministered to treat or prevent a particular disease are known by theskilled person as appropriate for the disease being treated.

In a further aspect of the present invention, the compounds of thepresent invention, may be combined with standard therapeutic agentswhich are commonly used for the treatment of the medical conditions asdescribed herein, more particularly selected from the group comprising,but not limited to methotrexate, corticosteroids like prednisone,prednisolone, methylprednisolone, dexamethasone, betamethasone,cortisone and the like; mycophenolate mofetil, tacrolimus, leflunomideor teriflunomide, cyclosporine A, cyclophosphamide, mitoxanthrone,fingolimod, azathioprine, glatiramer acetate, dimethyl fumarate, an IK-1inhibitor like TRAM-34, a JAK-inhibitor like Tofacitinib or braticinip,a SYK-inhibitor like Fostamatinib, interferon-beta (IFN-β).

The person skilled in the art is aware on the base of his/her expertknowledge of the total daily dosage(s) and administration form(s) of theadditional therapeutic agent(s) coadministered. Said total dailydosage(s) can vary within a wide range. In practicing the presentinvention and depending on the details, characteristics or purposes oftheir uses mentioned above, the compounds according to the presentinvention may be administered in combination therapy separately,sequentially, simultaneously or chronologically staggered (e.g. ascombined unit dosage forms, as separate unit dosage forms or a adjacentdiscrete unit dosage forms, as fixed or nonfixed combinations, askit-of-parts or as admixtures) with one or more standard therapeutics.In certain embodiments these standard therapeutics comprise art-knownchemotherapeutic or target specific anti-cancer agents.

Thus, a further aspect of the present invention is a combination orpharmaceutical composition comprising a first active ingredient, whichis a compound of the present invention or a salt or hydrate thereof, asecond active ingredient, which is an art-known standard therapeutic forthe medical conditions as described herein, and optionally apharmacologically acceptable carrier, diluent and/or excipient forsequential, separate, simultaneous or chronologically staggered use intherapy in any order, e.g. to treat, prevent or ameliorate the diseasesand/or medical conditions as described herein.

In this context, the present invention further relates to a combinationcomprising a first active ingredient, which is at least one compoundaccording to the present invention, and a second active ingredient,which is at least one art-known standard therapeutic for the medicalconditions as described herein, for separate, sequential, simultaneousor chronologically staggered use in therapy, such as e.g. in therapy ofthose diseases mentioned herein.

The term “combination” according to the present invention may be presentas a fixed combination, a non-fixed combination or a kit-of-parts. A“fixed combination” is defined as a combination wherein the said firstactive ingredient and the said second active ingredient are presenttogether in one unit dosage or in a single entity. One example of a“fixed combination” is a pharmaceutical composition wherein the saidfirst active ingredient and the said second active ingredient arepresent in admixture for simultaneous administration, such as in aformulation. Another example of a “fixed combination” is apharmaceutical combination wherein the said first active ingredient andthe said second active ingredient are present in one unit without beingin admixture.

A “kit-of-parts” is defined as a combination wherein the said firstactive ingredient and the said second active ingredient are present inmore than one unit. One example of a “kit-of-parts” is a combinationwherein the said first active ingredient and the said second activeingredient are present separately. The components of the kit-of-partsmay be administered separately, sequentially, simultaneously orchronologically staggered.

The first and second active ingredient of a combination or kit-of-partsaccording to the present invention may be provided as separateformulations (i.e. independently of one another), which are subsequentlybrought together for simultaneous, sequential, separate orchronologically staggered use in combination therapy; or packaged andpresented together as separate components of a combination pack forsimultaneous, sequential, separate or chronologically staggered use incombination therapy.

The type of pharmaceutical formulation of the first and second activeingredient of a combination or kit-of-parts according to the presentinvention can be similar, i.e. both ingredients are formulated inseparate tablets or capsules, or can be different, i.e. suited fordifferent administration forms, such as e.g. one active ingredient isformulated as tablet or capsule and the other is formulated for e.g.intravenous administration.

The amounts of the first and second active ingredients of thecombinations, compositions or kits according to the present inventionmay together be a therapeutically effective amount for the treatment,prophylaxis or amelioration of a medical condition as described herein.

A further aspect of the present invention is a method for treatingcotherapeutically the medical conditions as described herein, in apatient in need of such treatment comprising administering separately,sequentially, simultaneously, fixed or non-fixed a pharmacologicallyactive and therapeutically effective and tolerable amount of one or moreof the compounds according to the present invention and apharmacologically active and therapeutically effective and tolerableamount of one or more art-known therapeutic agents for the medicalconditions as described herein, to said patient.

For the production of the pharmaceutical compositions, the compounds ofthe present invention are suitably mixed with suitable pharmaceuticalauxiliaries and further processed to give suitable pharmaceuticalformulations. Suitable pharmaceutical formulations are, for example,powders, emulsions, suspensions, sprays, oils, ointments, fattyointments, creams, pastes, gels or solutions. The pharmaceuticalcompositions according to the invention are prepared by processes knownper se.

As used herein, the term “room temperature” or “r.t.” usually refers toabout 25° C.

Analytical Devices Used

Analytical LC/ESI-MS: Waters 2700 Autosampler. Waters 1525 MultisolventDelivery System. 5 μL sample loop. Column, Phenomenex Onyx MonolythicC18 50×2 mm, with stainless steel 2 μm prefilter. Eluent A, H₂O+0.1%HCOOH; eluent B, MeCN. Gradient, 5% B to 100% B within 3.80 min, thenisocratic for 0.20 min, then back to 5% B within 0.07 min, thenisocratic for 0.23 min; flow, 0.6 ml/min and 1.2 ml/min

Waters Micromass ZQ 4000 single quadrupol mass spectrometer withelectrospray source. MS method, MS4_15 minPM-80-800-35V;positive/negative ion mode scanning, m/z 80-800 in 0.5 s; capillaryvoltage, 3.50 kV; cone voltage, 50 V; multiplier voltage, 650 V; sourceblock and desolvation gas temperature, 120° C. and 300° C.,respectively. Waters 2487 Dual λ Absorbance Detector, set to 254 nm.Software, Waters Masslynx V 4.0.

Waters Micromass LCZ Platform 4000 single quadrupol mass spectrometerwith electrospray source. MS method, MS4_15 minPM-80-800-35V;positive/negative ion mode scanning, m/z 80-800 in 1 s; capillaryvoltage, 4.0 kV; cone voltage, 30 V; multiplier voltage, 900 V; sourceblock and desolvation gas temperature, 120° C. and 300° C.,respectively. Waters 996 Photodiode Array Detector, set 200 to 400 nm.Software, Waters Masslynx V4.0.

Values for [M+H]⁺ given in the examples are those found within thecorresponding LC/MS chromatogram for the respective compound. Thesevalues were all found within tolerable margins of +/−0.3 units comparedto calculated exact mass upon protonation of the compound.

Preparative thinlayer chromatography (preparative TLC): Merck PLCplates, silica gel 60 F254, 0.5 mm, 1.0 mm or 2.0 mm

Column chromatography: Acros silica gel 60A, 0.035-0.070 mm

Preparative HPLC-MS: Waters 2767 Autosampler, Waters 600 MultisolventDelivery System with analytical pump heads (100 μL); Waters 600Controller; Waters 2525 Binary Gradient Modul with preparative pumpheads (500 μL). At-Column-Dilution: solvent1, MeCN:H₂O 70:30 (v/v),solvent2, MeCN:MeOH:DMF 80:15:5 (v/v/v); flow rate, 5 mL/min Autosampler2767 with 10 mL syringe and 10 mL Sample loop. Column 6-position valveFlom 401 with Waters X-Terra RP18, 5 μm, 19×150 mm with X-Terra RP18guard cartridge 5 μm, 19×10 mm, used at flow rate 20 mL/min; WatersSunFire Prep OBD 5 μm, 30×50 mm with SunFire RP18 guard cartridge 5 μm,19×10 mm, used at flow rate 25 mL/min; Waters Atlantis Prep T3 OBD 5 μm,30×50 mm with Atlantis guard cartridge, used at flow rate 50 mL/min;Waters X-Bridge Prep OBD 5 μm, 19×150 mm with X-Bridge RP18 guardcartridge 5 μm, 19×10 mm used at flow rate 20 mL/min; Waters AtlantisPrep T3 OBD 5 μm, 19×50 mm with Atlantis guard cartridge, used at flowrate 25 mL/min and YMC-Actus Hydrosphere C18 5 μm, 20×50 mm with Actusguard cartridge, used at flow rate 20 mL/min Eluent A, H₂O containing0.1% (v/v) HCO₂H or H₂O containing 0.1% (v/v) NEt₃; eluent B, MeCN.Different linear gradients, individually adapted to sample. Injectionvolume, 9 mL, depending on sample. Make-up solvent, MeOH-MeCN—H₂O—HCO₂H80:15:4.95:0.05 (v/v/v/v). Make-up pump, Waters Reagent Manager, flowrate 0.5 mL/min. Waters ZQ single quadrupole mass spectrometer withelectrospray source. Positive or negative ion mode scanning m/z 105-950in 1 s; capillary, 3.6 kV; cone voltage, 45 V; multiplier voltage, 700V; probe and desolvation gas temperature, 120° C. and 250° C.,respectively. Waters Fraction Collector 2767 with mass or UV-triggeredfraction collection. Waters 2487 Dual λ Absorbance Detector, set to 254nm. Software, Waters Masslynx V 4.0 SP4.

¹H NMR spectra were recorded at room temperature on a BrukerSupraleitendes Fourier NMR Spektrometer, Avance™ 300 MHz. Chemicalshifts δ are reported in ppm. Multiplicity of a certain signal (singlet,doublet, triplet, quartet, multiplet) is indicated by the respectiveabbreviation (s, d, t, q, m respectively). “br s” indicates a broadsinglet, “m_(C)” a centered multiplet. The solvent residual signals wereused as internal standards: δ (CDCl₃)=7.26, δ (d6-DMSO)=2.50, δ(CD₃OD)=3.31, δ (d6-acetone)=2.05.

Eluents for Preparative TLC or Column Chromatography (CC) on Silica Gel:

Eluent1: petroleum ether/CH₂Cl₂/MeOH; Eluent2: CH₂Cl₂/MeOH; Eluent3:petroleum ether/ethyl acetate; for each eluent, the aforementionedsolvents were used in different ratios, depending on the respectivecompound

Standard Protocols and Syntheses of Building Blocks:

If not commercially available, required β-ketoesters b1 (Scheme 1) weresynthesized via Claisen condenzation from appropriately substitutedbenzoic acid esters and respective alpha-substituted acetic acid estersaccording to Taber et al., J. Org. Chem. 1995, 60, 1093 and Müller etal., Helvetica Chim. Acta 1998, 81, 317, the synthesis protocols ofwhich are incorporated herein by reference. The desired building blockswere obtained in the β-ketoester tautomeric form as the sole or majorcomponent, accompanied in most cases by their tautomeric form alkyl3-hydroxy-3-aryl-2-propenoate: ethyl3-(2-fluorophenyl)-2-methyl-3-oxopropanoate, ethyl3-(2-ethoxyphenyl)-2-methyl-3-oxopropanoate, ethyl3-(2-methoxyphenyl)-2-methyl-3-oxopropanoate, ethyl3-(3-methoxyphenyl)-2-methyl-3-oxopropanoate, ethyl2-methyl-3-oxo-3-phenylpropanoate, methyl3-(2-chlorophenyl)-2-methyl-3-oxopropanoate, ethyl2-methyl-3-oxo-3-(pyridin-3-yl)propanoate, methyl3-(2-methoxypyridin-3-yl)-2-methyl-3-oxopropanoate, methyl3-(4-methoxypyridin-3-yl)-2-methyl-3-oxopropanoate, methyl2-methyl-3-(o-tolyl)-3-oxopropanoate.

Exemplarily given is the NMR for ethyl2-methyl-3-oxo-3-phenylpropanoate, which was obtained only within theβ-ketoester form: ¹H NMR (300 MHz, CDCl₃): δ=1.16 (3H, t, OEt), 1.49(3H, d, Me), 4.15 (2H, q, OEt), 4.37 (1H, q, CH), 7.47 (2H, tt, Ar—H),7.58 (1H, tt, Ar—H), 7.98 (2H, dt, Ar—H). Likewise exemplarily given isthe NMR for methyl 3-(2-chlorophenyl)-2-methyl-3-oxopropanoate, whichwas obtained as a 3:2 mixture with its tautomer: ¹H NMR (300 MHz,CDCl₃): δ=1.48 (3H, d, Me, keto), 1.59 (3H, s, Me, enol), 3.68 (3H, s,OMe, keto), 3.85 (3H, s, OMe, enol), 4.35 (1H, q, CH, keto), 7.30-7.49(4H keto+4H enol, m, Ar—H), 12.57 (1H, s, OH, enol).

Standard Procedure 1 (SP-1): Synthesis of Furocoumarins (Cf. Scheme 1)

SP-1A (adapted from J. Org. Chem. 1962, 27, 3703): The respectiveresorcinol a (0.36 to 4.0 mmol, 1.0 eq.) was treated with the respectiveβ-ketoester b1 (1.0 eq.) and trifluoroacetic acid (1-2 mL/mmol) underreflux overnight. The reaction was quenched by addition of iced water.The mixture was extracted thrice with ethyl acetate, combined organicphases were washed once with aq. NaHCO₃ (5%) and dried over MgSO₄ togive crude coumarin c1.

SP-1B (adapted from Heterocyclic Commun. 1997, 3, 339; Chem. Nat. Comp.2000, 36, 478; Chem. Nat. Comp. 2002, 38, 539): Equivalents (eq.) arereferred to with respect to the amount of resorcinol used in SP-1A.

1^(st) step: The crude coumarin c1 was dissolved in acetone (10 mL/mmol;for larger scale, 5 mL/mmol were used), K₂CO₃ (2.0 e.q), NaI (0.3 eq.)and the respective alpha-halo-ketone d1 (1.6 eq.) were added, and themixture stirred under reflux overnight. Salts were filtered off, thecake was washed with acetone and the filtrate was concentrated todryness.

2nd step: The crude mixture was taken up in iPrOH (3-10 mL/mmol) andtreated with 1.0 N aq. NaOH (3-10 mL/mmol) at 80° C. for 5 h. Themixture was cooled to room temperature and acidified with 5% aq. HCl (topH 1-2). Further H₂O was added and the resulting suspension was storedat about 4° C. overnight. Depending on the outcome, either a precipitatewas filtered off and washed with 5% aq. NaHCO₃, deionized water andfinally with Et₂O (SP-1B-1) or in the case of a cloudy mixture, saidmixture was extracted with ethyl acetate or CH₂Cl₂, the combined organicphases were washed with saturated aq. NaHCO₃, dried over MgSO₄ andpurified by preparative TLC or column chromatography on silica gel forlarger scale syntheses (SP-1B-2) to give furocoumarins e.

3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one (e1) was synthesizedaccording to SP-LA using 2-methylresorcinol and ethyl benzoylacetate;53% yield (30 mmol; the product precipitated upon cooling the reactionmixture to r.t., was filtered off and washed with water and MeOH, or thereaction mixture was diluted with water and extracted with ethylacetate) and SP-1B-1 (using chloroacetone d2; final purification bysilica gel column chromatography, from 100% petroleum ether toeluent3-6:4, and re-crystallization from MeOH).

7-hydroxy-8-methyl-4-phenyl-2H-chromen-2-one (c1, Scheme 1): ¹H NMR (300MHz, d₆-DMSO): δ=2.21 (3H, d, Me), 6.12 (1H, s, Ar—H), 6.84 (1H, d,Ar—H), 7.11 (1H, d, Ar—H), 7.45-7.59 (5H, m, Ar—H), 10.49 (1H, s, OH).

3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one (e1): LC/MS [M+H]±:290.93; ¹H NMR (300 MHz, CDCl₃): δ=2.16 (3H, d, Me), 2.63 (3H, s, Me),6.31 (1H, s, Ar—H), 7.37 (1H, s, Ar—H), 7.45 (1H, m, Ar—H), 7.47-7.51(2H, m, Ar—H), 7.52-7.58 (3H, m, Ar—H). ¹H NMR (300 MHz, d6-DMSO):δ=2.12 (3H, d, Me), 2.53 (3H, s, Me), 6.34 (1H, s, Ar—H), 7.37 (1H, s,Ar—H), 7.56-7.62 (5H, m, Ar—H), 7.88 (1H, m, Ar—H).

Bromination of 3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one (e1)

(e1) (3.4 mmol) was dissolved in CH₂Cl₂ and AcOH (each 4.5 mL/mmol).N-Bromosuccinimide (1.2 eq., in CH₂Cl₂, 2 mL/mmol) was added, and themixture was stirred at r.t. for 1 h, and then diluted with CH₂Cl₂ andwashed with 5% aq. NaHCO₃. The organic phase was dried over MgSO₄,filtered and concentrated in vacuo. If necessary, the residue waspurified by preparative TLC (CH₂Cl₂ 100%); 84-96% yield.2-bromo-3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one (f): LC/MS[M+H]±: 368.90; ¹H NMR (300 MHz, CDCl₃): δ=2.11 (3H, d, Me), 2.63 (3H,s, Me), 6.33 (1H, s, Ar—H), 7.29 (1H, s, Ar—H), 7.45-7.51 (2H, m, Ar—H),7.53-7.61 (3H, m, Ar—H).

Chloromethylation of 3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one(e1)

Chloromethyl methyl ether (25 eq.) was added to a solution of (e1) (3.4mmol) in HOAc (22 mL/mmol), and stirred at r.t. overnight. Additionalchloromethyl methyl ether (25 eq.) was added and the mixture stirred atr.t. for further 24 h, then poured onto an ice/water mixture, and theresulting precipitate was filtered off, washed with water and dried.Crude product was purified by silica gel column chromatography(eluent3—4:1); 11% yield.2-(chloromethyl)-3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one (h):LC/MS [M+H]±: 338.86; ¹H NMR (300 MHz, CDCl₃): δ=2.19 (3H, d, Me), 2.65(3H, s, Me), 4.72 (2H, s, CH₂), 6.33 (1H, s, Ar—H), 7.35 (1H, s, Ar—H),7.39-7.51 (2H, m, Ar—H), 7.52-7.58 (3H, m, Ar—H).

Standard Procedure 2 (SP-2): Synthesis of Furoquinolones (Cf. Scheme 3)

SP-2A

3-Amino-o-cresol (k1) (1.0 eq.) and the respective methyl/ethyl3-aryl-3-oxo-propanoate b2 (1.0 eq.) were mixed and heated at 145° C.for 5 h to give predominantlyN-(3-hydroxy-2-methylphenyl)-3-oxo-3-arylpropanamide, which was thencyclized by treatment of the slurry with TFA (2.5 mL/mmol) for 1-3 h at72° C. Addition of an ice/water mixture resulted in precipitation, whichwas filtered off and washed with water to give crude7-hydroxy-8-methyl-4-arylquinolin-2(1H)-one l1 (SP-2A-1). In analternative workup (SP-2A-2), the mixture was partitioned between waterand ethyl acetate, combined organic phases were washed with brine anddried over MgSO₄, and the crude product was purified by columnchromatography (eluent3, 1:1).

SP-2B

7-hydroxy-8-methyl-4-arylquinolin-2(1H)-one l1 (1.0 eq.) was suspendedin CH₂Cl₂ (5 mL/mmol) and DMSO (0.75 mL/mmol) and cooled to −10° C.Diisopropylamine (0.5 eq.) was added, followed by a dropwise addition ofN-bromosuccinimide [NBS; 1.0 eq., dissolved in CH₂Cl₂ (2.5 mL/mmol) andDMSO (0.38 mL/mmol)]. This solution was stirred at −10° C. for 1 h,before NBS was added slowly again [0.5 eq., dissolved in CH₂Cl₂ (2.5mL/mmol) and DMSO (0.38 mL/mmol)]. The latter step was repeated oncemore, before the mixture was partitioned between CH₂Cl₂ and 0.5 M aq.HCl. Combined organic phases were washed with saturated aq. NaHCO₃ anddried over MgSO₄. Chromatography on silica gel gave3,6-dibromo-7-hydroxy-8-methyl-4-arylquinolin-2(1H)-one m1.

SP-2C (1^(st) step adapted from J. Med. Chem. 2004, 47, 6392 and Chem.Pharm. Bull. 1983, 852)

1^(st) step: 3,6-dibromo-7-hydroxy-8-methyl-4-arylquinolin-2(1H)-one m1(1.0 eq.) was dissolved in iPrOH (5 mL/mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (1.5 eq.) and treated withchloroacetone (d2) (1.2 eq.) at 80° C. for 2.5 h. In case of incompleteconversion, the aforementioned quantities of DBU and chloroacetone (d2)were added again and stirring was continued at 80° C. for 1.5 h. Themixture was partitioned between CH₂Cl₂ or ethyl acetate and water.Combined organic phases were washed with citric acid (5%, aq.) and brineand dried over MgSO₄. Isolation of3,6-dibromo-8-methyl-7-(2-oxopropoxy)-4-arylquinolin-2(1H)-one wasachieved by chromatography on silica gel.

2^(nd) step:3,6-dibromo-8-methyl-7-(2-oxopropoxy)-4-arylquinolin-2(1H)-one (1.0 eq.)was dissolved in DMF (30 mL/mmol) in an argon atmosphere. Nickel(II)chloride (0.33 eq.) and chromium(II) chloride (10 eq.) were added andthe mixture was stirred at 125° C. for 1-2 h. Salts were removed byfiltration, the filter cake was washed with DMF. The filtrate waspartitioned between CH₂Cl₂ or ethyl acetate and 1.0 M aq. HCl. Combinedorganic phases were washed with brine and dried over MgSO₄. Purificationwas achieved by preparative TLC (eluent1—4:6:1) to usually give3,9-dimethyl-5-arylfuro[3,2-g]quinolin-7(8H)-one n1 (R²═H) as the majorproduct and 6-bromo-3,9-dimethyl-5-arylfuro[3,2-g]quinolin-7(8H)-one n1(R²═Br) as a minor by-product.

Standard Procedure 3 (SP-3): Synthesis of Furoquinolones (Cf. Scheme 4)

SP-3A

1^(st) step: The respective methyl/ethyl 3-aryl-2-methyl-3-oxopropanoateor methyl/ethyl 3-aryl-3-oxopropanoate b1 (1.1 eq.) was dissolved intrans-decahydronaphthalene (1 mL/mmol; =trans-decalin). The respective3-amino-o-cresol k1 or k2 (1.0 eq.) was added, and the resulting mixturewas stirred for 5-10 h at 170° C. Upon cooling to room temperature, thesolvent was decanted, and the residue was washed with petroleum ether.The resulting 3-aryl-N-(3-hydroxy-2-methylphenyl)-3-oxopropanamide wasdried in vacuo.

2^(nd) step: 3-aryl-N-(3-hydroxy-2-methylphenyl)-3-oxopropanamide wascyclized in TFA (3 mL/mmol) for 2 h at 72° C. TFA was removed underreduced pressure, and the residue was partitioned between water andethyl acetate. Combined organic layers were washed with saturated aq.NaHCO₃ and brine, dried over Na₂SO₄ and concentrated in vacuo. Therespective intermediate 4-aryl-7-hydroxy-8-methylquinolin-2(1H)-one 12was purified by chromatography on silica gel.

SP-3B

4-aryl-7-hydroxy-8-methylquinolin-2(1H)-ones l2 with varioussubstituents in position 3 were dissolved in CH₂Cl₂/DMSO (2:1; 5mL/mmol) and cooled to 0° C. A solution of NBS (1.4 eq.) in DMSO (0.35mL/mmol NBS) was added, and the resulting mixture was stirred for 1 h at0° C. If a reaction control by TLC indicated incomplete conversion,additional NBS (1.4 eq.) was added as solid in one portion, and stirringwas continued for 1 h at 0° C. The reaction mixture was quenched withsaturated aq. Na₂SO₃, diluted with water and extracted with EtOAc.Combined organic layers were washed with 1 N aq. HCl and brine, driedover Na₂SO₄ and concentrated in vacuo to afford the respective crude3-substituted-6-bromo-4-aryl-7-hydroxy-8-methylquinolin-2(1H)-ones m2.

SP-3C

1^(st) step: Differently3-substituted-6-bromo-4-aryl-7-hydroxy-8-methylquinolin-2(1H)-ones m2(1.0 eq.) were suspended in iPrOH (6.0 mL/mmol). DBU (1.8 eq.) and allylbromide (1.7 eq.) were added, and the resulting mixture was heated to80° C. for 2 h. The reaction mixture was diluted with water and theresulting precipitate was filtered off, washed with water and dried invacuo to give the respective crude O-allylated compound. If insufficientprecipitation occurred, the mixture (or alternatively supernatant andrinsing solutions from precipitation) was partitioned between H₂O andCH₂Cl₂.

2^(nd) step: The respective crude7-(allyloxy)-6-bromo-8-methyl-4-phenylquinolin-2(1H)-one derivate (1.0eq.), tetrabutylammonium chloride hydrate (1.1 eq.), sodium formiate(1.0 eq.), Na₂CO₃ (2.5 eq.) and Pd(OAc)₂ (0.2 eq.) were placed in ascrew cap vial. DMF (20 mL/mmol) was added, and the resulting mixturewas degassed by bubbling argon through the solution. The mixture wasthen stirred at 90° C. under an argon atmosphere for 1-16 h. The mixturewas diluted with water and extracted with EtOAc. The combined organiclayers were washed with 1 N aq. NaOH and brine, dried over Na₂SO₄ andconcentrated in vacuo. The respective product n3 was purified bychromatography on silica gel.

SP-4 (Cf. Scheme 3): N/O-Methylation of Furoquinolones

The respective 3,9-dimethyl-5-phenylfuro[3,2-g]quinolin-7(8H)-one(bearing different 6-substituents) n1 (1.0 eq.) was dissolved in DMF (1mL/0.1 mmol). K₂CO₃ (3.0 eq.) and iodomethane (2.5 eq.) were added, andthe mixture was heated to 90° C. for 2 h. The suspension was filtered,the filter cake was washed with ethyl acetate, and the filtrate wasextracted with citric acid (5%, aq.) and brine. The organic phase wasdried over MgSO₄ and product isolation (n2 and o) was achieved bypreparative TLC (eluent1—10:6:1).

SP5: Synthesis of Isoxazolocoumarins and Isoxazoloquinolones (cf. Scheme5)

SP-5A:

6-bromo-7-hydroxy-3,8-dimethyl-4-aryl-2H-chromen-2-one or differentlyN-substituted 6-bromo-7-hydroxy-3,8-dimethyl-4-arylquinolin-2(1H)-one m3(1.0 eq.) and PdCl₂(PPh₃)₂ (0.15 eq.) were placed in a microwave vial.DMF (4.0 mL/mmol) and 1-ethoxyvinyl-tri-n-butyltin (1.1 eq.) were added,and the resulting mixture was heated in the microwave to 160° C. for 15min Additional PdCl₂(PPh₃)₂ (0.05 eq.) and 1-ethoxyvinyl-tri-n-butyltin(0.5 eq.) were added, and the mixture was again heated in the microwaveto 160° C. for 15 min 1 N aq. HCl was added, and the mixture was stirredat rt. for 30 min After dilution with water, the mixture was extractedwith EtOAc. Combined organic layers were washed with water and brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified bychromatography on silica gel to give the respective 6-acetyl derivativep.

SP-5B: (Alternative to SP-5A: Fries Rearrangement)

1^(st) step: The respective and potentially further substituted7-hydroxy-8-methyl-4-aryl-2H-chromen-2-one or7-hydroxy-8-methyl-4-arylquinolin-2(1H)-one 13 (1.0 eq.) was dissolvedin pyridine (3 mL/mmol). Acetyl chloride (2.0 eq.) was added, and theresulting mixture was stirred at rt. for 18 h. If a reaction control byTLC showed incomplete conversion, additional acetyl chloride (2.0 eq.)was added, and stirring was continued at rt. for 17 h. In case of poorsolubility of the starting material, NMP might be added. The reactionmixture was diluted with water and extracted with CH₂Cl₂ or ethylacetate. The combined organic layers were washed with saturated NaHCO₃,dried over Na₂SO₄ and concentrated in vacuo. Crude product (potentiallyfurther substituted 7-acetoxy-8-methyl-4-aryl-2H-chromen-2-one or7-acetoxy-8-methyl-4-arylquinolin-2(1H)-one) was directly used for thesubsequent Fries rearrangement

2^(nd) step (in analogy to J. Ind. Chem. Soc. 1969, 46, 1014 and ARKIVOC2000, 6, 931): The respective and potentially further substituted7-acetoxy-8-methyl-4-aryl-2H-chromen-2-one or7-acetoxy-8-methyl-4-arylquinolin-2(1H)-one (1.0 eq.) and AlCl₃ (5.0eq.) were heated neat to 170° C. (the mixture became liquid/oily atapproximately 145° C.) and stirred at this temperature for 2.5 h. Thereaction mixture was cooled to room temperature and treated with 1 N aq.HCl (sonication). The resulting suspension was diluted with water andextracted with CH₂Cl₂ or ethyl acetate. The combined organic layers weredried over Na₂SO₄ and concentrated in vacuo. The residue was purified bypreparative TLC (eluent2) to give the respective, optionally furthersubstituted 6-acetyl-7-hydroxy-8-methyl-4-aryl-2H-chromen-2-one or6-acetyl-7-hydroxy-8-methyl-4-arylquinolin-2(1H)-one derivative p.

SP-5C:

The respective, optionally further substituted6-acetyl-7-hydroxy-8-methyl-4-aryl-2H-chromen-2-one or6-acetyl-7-hydroxy-8-methyl-4-arylquinolin-2(1H)-one derivative p (1.0eq.), H₂NOH.HCl (5.0 eq.) and NaAc (5.0 eq.) were suspended in MeOH (7mL/mmol) and heated under reflux for 3 h, then concentrated, and theresidue was partitioned between water and EtOAc. The aqueous layer wasextracted with EtOAc. Combined organic layers were washed with water andbrine, dried over Na₂SO₄ and concentrated in vacuo. The resulting crudeproduct was suspended in acetic anhydride (7.0 mL/mmol), and CH₂Cl₂,dioxane, DMF or NMP was added to improve solubility. The mixture wasstirred at rt. for 24 h. The reaction mixture was diluted with water andstirred for 15 min. If a precipitate was formed, it was filtered off,washed with water and taken up in CH₂Cl₂. This organic phase was driedover Na₂SO₄. If no or insufficient precipitation occurred, the mixturewas extracted with ethyl acetate, the combined organic layers werewashed with saturated aq. NaHCO₃ and brine and dried over Na₂SO₄. Ineither of the aforementioned cases, the solvent was removed in vacuo andthe resulting intermediate was cyclized by treatment with K₂CO₃ (2.2eq.) in a toluene suspension (7 mL/mmol) at 110° C. for 2 h. Toluene wasremoved in vacuo. The residue was suspended in CH₂Cl₂ and filtered. Thefiltrate was concentrated, and the residue was purified by silica gelchromatography to yield the desired product q.

EXAMPLES OF COMPOUNDS OF THE PRESENT INVENTION

Most synthetic procedures are referring to the above Standard Procedures(SP). Where applicable, deviations from the SP are detailed inparentheses, whereas unmentioned steps have been performed in accordancewith the SP protocol and are thus not named explicitly again.

Note that examples 26-34, 36, 40, 49, 51, 52, 54-56, 59-61 and 64 arenot part of the present invention and serve as illustrative examples.

Example 1: 5-(2-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one

Synthesized from ethyl (2-methoxybenzoyl)acetate and 2-methylresorcinolaccording to SP-1A (0.36 mmol), followed by SP-1B-2 using chloroacetone(d2) (preparative TLC, eluent1—4:6:1; or CC, eluent3—4:1); 23% yield. ¹HNMR (300 MHz, CDCl₃): δ=2.13 (3H, d, Me), 2.63 (3H, s, Me), 3.75 (3H, s,OMe), 6.30 (1H, s, Ar—H), 7.08 (1H, dd, Ar—H), 7.09 (1H, s, Ar—H), 7.12(1H, td, Ar—H), 7.27 (1H, dd, Ar—H), 7.43 (1H, m, Ar—H), 7.51 (1H, td,Ar—H); [M+H]⁺ (HPLC/MS): 321.08.

Example 2: 5-(3-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one

Synthesized from ethyl (3-methoxybenzoyl)acetate and 2-methylresorcinolin 11% yield according to SP-1A (0.36 mmol), followed by SP-1B-2 usingchloroacetone (d2) (preparative TLC, eluent1—4:6:1). ¹H NMR (300 MHz,CDCl₃): δ=2.17 (3H, d, Me), 2.64 (3H, s, Me), 3.88 (3H, s, OMe), 6.32(1H, s, Ar—H), 7.01 (1H, m, Ar—H), 7.05-7.10 (2H, m, Ar—H), 7.40 (1H, s,Ar—H), 7.45 (1H, t, Ar—H), 7.46 (1H, m, Ar—H); [M+H]⁺ (HPLC/MS): 321.05.

Example 3: 5-(2-chlorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one

Synthesized from ethyl (2-chlorobenzoyl)acetate and 2-methylresorcinolin 25% yield according to SP-1A (0.64 mmol), followed by SP-1B-2 usingchloroacetone (d2) (preparative TLC, eluent3—3:1). ¹H NMR (300 MHz,CDCl₃): δ=2.13 (3H, d, Me), 2.64 (3H, s, Me), 6.30 (1H, s, Ar—H), 6.97(1H, s, Ar—H), 7.35 (1H, dd, Ar—H), 7.44 (1H, td, Ar—H), 7.45 (1H, m,Ar—H), 7.49 (1H, td, Ar—H), 7.58 (1H, dd, Ar—H); [M+H]⁺ (HPLC/MS):325.07.

Example 4:3,9-dimethyl-5-(3-(trifluoromethyl)phenyl)-7H-furo[3,2-g]chromen-7-one

Synthesized from ethyl (3-trifluoromethylbenzoyl)acetate and2-methylresorcinol according to SP-1A (0.81 mmol), followed by SP-1B-1(using chloroacetone d2) and preparative TLC (eluent1—4:6:1) for thefiltrate; 36% yield. ¹H NMR (300 MHz, CDCl₃): δ=2.16 (3H, d, Me), 2.64(3H, s, Me), 6.33 (1H, s, Ar—H), 7.23 (1H, s, Ar—H), 7.48 (1H, m, Ar—H),7.67-7.73 (2H, m, Ar—H), 7.76 (1H, s, Ar—H), 7.80-7.85 (1H, m, Ar—H);[M+H]⁺ (HPLC/MS): 359.03.

Example 5:5-(2-fluorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one

Synthesized from ethyl 3-(2-fluorophenyl)-2-methyl-3-oxopropanoate and2-methylresorcinol in 23% yield according to SP-1A (4.0 mmol; reactiontime was 5.5 h, coumarin c1 was purified by preparative TLC, eluent37:3), followed by SP-1B-2 (2.6 eq. chloroacetone d2; preparative TLC,CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ=2.00 (3H, s, Me), 2.10 (3H, d, Me),2.63 (3H, s, Me), 6.86 (1H, s, Ar—H), 7.22-7.32 (2H, m, Ar—H), 7.35 (1H,td, Ar—H), 7.42 (1H, m, Ar—H), 7.49-7.58 (1H, m, Ar—H); [M+H]⁺(HPLC/MS): 322.89.

Example 6:5-(3-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one

Synthesized from ethyl 3-(3-methoxyphenyl)-2-methyl-3-oxopropanoate and2-methylresorcinol in 17% yield according to SP-1A (1.0 mmol), followedby SP-1B-2 (2.6 eq. chloroacetone d2; preparative TLC, eluent1—4:6:1).¹H NMR (300 MHz, CDCl₃): δ=2.21 (3H, d, Me), 2.42 (3H, s, Me), 2.67 (3H,s, Me), 3.82 (3H, s, OMe), 7.03-7.12 (2H, m, Ar—H), 7.39 (1H, m, Ar—H),7.33-7.45 (2H, m, Ar—H); [M+H]⁺ (HPLC/MS): 334.88.

Example 7:5-(2-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one

Synthesized from ethyl 3-(2-methoxyphenyl)-2-methyl-3-oxopropanoate and2-methylresorcinol in 29% yield according to SP-1A (2.0 mmol), followedby SP-1B-2 (2.6 eq. chloroacetone d2; intermediate was dissolved inCH₂Cl₂ and filtered through silica gel, final product was purified bypreparative TLC, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ=1.94 (3H, s, Me),2.09 (3H, d, Me), 2.63 (3H, s, Me), 3.74 (3H, s, OMe), 6.86 (1H, s,Ar—H), 7.07-7.16 (3H, m, Ar—H), 7.40 (1H, m, Ar—H), 7.45-7.54 (1H, m,Ar—H); [M+H]⁺ (HPLC/MS): 334.86.

Example 8: 5-(2-fluorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one

Synthesized from ethyl (2-fluorobenzoyl)acetate and 2-methylresorcinolaccording to SP-1A (4.0 mmol), followed by SP-1B-1 (using chloroacetoned2) and final purification by column chromatography (eluent2—9:1); 31%yield. ¹H NMR (300 MHz, d6-DMSO): δ=2.11 (3H, d, Me), 2.55 (3H, s, Me),6.46 (1H, s, Ar—H), 7.16 (1H, d, Ar—H), 7.41-7.50 (2H, m, Ar—H), 7.56(1H, td, Ar—H), 7.62-7.70 (1H, m, Ar—H), 7.89 (1H, m, Ar—H); [M+H]⁺(HPLC/MS): 309.12.

Example 9: 3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one

Synthesized from ethyl 2-methyl-3-oxo-3-phenyl-propanoate and2-methylresorcinol in 52% yield according to SP-1A (4.0 mmol), followedby SP-1B-1 (2.6 eq. chloroacetone d2; intermediate was dissolved inCH₂Cl₂ and filtered through silica gel), final purification by furthersilica gel filtration (CH₂Cl₂) and re-crystallization from EtOH. ¹H NMR(300 MHz, CDCl₃): δ=1.98 (3H, s, Me), 2.09 (3H, d, Me), 2.64 (3H, s,Me), 6.88 (1H, s, Ar—H), 7.27 (1H, dd, Ar—H), 7.42 (1H, m, Ar—H),7.47-7.61 (3H, m, Ar—H); [M+H]⁺ (HPLC/MS): 305.16.

Example 10:5-(2-ethoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one

Synthesized from ethyl 3-(2-ethoxyphenyl)-2-methyl-3-oxopropanoate and2-methylresorcinol in 5% yield according to SP-1A (2.0 mmol), followedby SP-1B-2 (2.6 eq. chloroacetone d2; preparative TLC, CH₂Cl₂). ¹H NMR(300 MHz, CDCl₃): δ=1.18 (3H, t, OEt), 1.96 (3H, s, Me), 2.09 (3H, d,Me), 2.63 (3H, s, Me), 4.01 (2H, qd, OEt), 6.88 (1H, s, Ar—H), 7.05-7.14(3H, m, Ar—H), 7.40 (1H, m, Ar—H), 7.42-7.50 (1H, m, Ar—H); [M+H]⁺(HPLC/MS): 348.87.

Example 11:5-(2-chlorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one

Synthesized from methyl 3-(2-chlorophenyl)-2-methyl-3-oxopropanoate and2-methylresorcinol according to SP-1A (0.48 mmol), followed by SP-1B-2(2.6 eq. chloroacetone d2; preparative TLC, eluent3—9:1); 4% yield. ¹HNMR (300 MHz, CDCl₃): δ=1.96 (3H, s, Me), 2.10 (3H, d, Me), 2.64 (3H, s,Me), 6.73 (1H, s, Ar—H), 7.21-7.26 (1H, m, Ar—H), 7.42 (1H, m, Ar—H),7.43-7.52 (1H, m, Ar—H), 7.58-7.63 (1H, m, Ar—H); [M+H]⁺ (HPLC/MS):339.14.

Example 12:3,9-dimethyl-2-morpholino-5-phenyl-7H-furo[3,2-g]chromen-7-one (cf.Scheme 2, g)

In a sealed tube in an argon atmosphere, 70 mg of2-bromo-3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one (f1) (0.19mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd₂dba₃, 0.05 eq.),2-(di-t-butylphosphino)biphenyl (0.2 eq.) and sodium tert-pentoxide (1.4eq.) were mixed in toluene (2 mL/mmol). After addition of morpholine(1.2 eq.), the mixture was stirred at 110° C. overnight. The mixture wasfiltrated through cotton wool, the filtrate was concentrated, and theresidue was purified twice via preparative TLC (eluent3—2:1; followed bya second chromatography with petroleum ether/ethyl acetate/MeOH—6:3:1)to give the title compound in 13% yield. ¹H NMR (300 MHz, CDCl₃): δ=2.07(3H, s, Me), 2.59 (3H, s, Me), 3.31 (4H, t, morpholinyl), 3.85 (4H, t,morpholinyl), 6.28 (1H, s, Ar—H), 7.14 (1H, s, Ar—H), 7.46-7.56 (5H, m,Ar—H); [M+H]⁺ (HPLC/MS): 375.94.

Example 13:3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile (cf.Scheme 2, g)

2-bromo-3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one (f1) (0.3mmol), CuCN (4.0 eq.), Pd₂dba₃ (0.2 eq.) and1,1′-bis(diphenylphosphino)ferrocene (1.6 eq.) were suspended in dioxane(5 mL), and the mixture was stirred at 100° C. for 5 h. The reactionmixture was diluted with ethyl acetate and filtrated over Celite®. Thefiltrate was washed with 5% aq. NaHCO₃, brine and H₂O. The organic layerwas dried over MgSO₄ and concentrated. The residue was purified viapreparative TLC (eluent3—2:1) to give the title compound in 10% yield.¹H NMR (300 MHz, CDCl₃): δ=2.38 (3H, s, Me), 2.65 (3H, s, Me), 6.37 (1H,s, Ar—H), 7.45-7.48 (3H, m, Ar—H), 7.55-7.59 (3H, m, Ar—H); [M+H]⁺(HPLC/MS): 315.93.

Example 14:3,9-dimethyl-2-(morpholinomethyl)-5-phenyl-7H-furo[3,2-g]chromen-7-one(cf. Scheme 2, i)

A mixture of2-(chloromethyl)-3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one (h1)(0.07 mmol), morpholine (2.0 eq.) and K₂CO₃ (3.0 eq.) in acetonitrile(14 mL/mmol) was stirred at reflux for 16 h, followed by cooling to rt.,filtration, washing with acetonitrile, and concentrating in vacuo.Excess morpholine was removed by coevaporation with toluene. The residuewas purified by preparative TLC (eluent2—95:5); yield: 27%. ¹H NMR (300MHz, CDCl₃): δ=2.29 (3H, s, Me), 2.64 (3H, s, Me), 3.12 (4H, br s,morpholinyl), 4.05 (4H, br s, morpholinyl), 4.25 (2H, br s, CH₂), 6.34(1H, s, Ar—H), 7.40 (1H, s, Ar—H), 7.44-7.50 (2H, m, Ar—H), 7.53-7.58(3H, m, Ar—H); [M+H]⁺ (HPLC/MS): 389.94.

Example 15:2-((dimethylamino)methyl)-3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one(cf. Scheme 2, i)

In a closed vial,2-(chloromethyl)-3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one (h1)(0.12 mmol) and KI (0.1 eq.) in THF (1.5 mL/mmol) were treated withdimethylamine (2 M in THF, 10 eq.) at 65° C. for 90 min, thenpartitioned between EtOAc and 2 M aq. NaOH. The organic phase was driedover MgSO₄ and concentrated in vacuo. Crude product was purified viapreparative TLC (eluent2—95:5); yield: 61%. ¹H NMR (300 MHz, CDCl₃):δ=2.14 (3H, s, Me), 2.32 (6H, s, NMe₂), 2.63 (3H, s, Me), 3.59 (2H, s,CH₂), 6.29 (1H, s, Ar—H), 7.31 (1H, s, Ar—H), 7.46-7.57 (5H, m, Ar—H);[M+H]⁺ (HPLC/MS): 347.94.

Example 16: 3-ethyl-6,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one

Synthesized from ethyl 2-methyl-3-oxo-3-phenyl-propanoate and2-methylresorcinol in 21% yield according to SP-1A (4.0 mmol), followedby SP-1B-1 using 1-bromo-2-butanone (2.6 eq.; the product precipitatedand was filtered off, taken up in CH₂Cl₂ and filtered through a pad ofsilica gel with CH₂Cl₂ as eluent). ¹H NMR (300 MHz, CDCl₃): δ=1.20 (3H,t, Et), 1.98 (3H, s, Me), 2.52 (2H, qd, Et), 2.63 (3H, s, Me), 6.90 (1H,s, Ar—H), 7.23-7.28 (2H, m, Ar—H), 7.41 (1H, t, Ar—H), 7.47-7.59 (3H, m,Ar—H); [M+H]⁺ (HPLC/MS): 318.89.

Example 17: 3-methyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one

This compound was synthesized from ethyl 3-oxo-3-o-tolylpropanoate andresorcinol in 10% yield according to SP-1A (0.7 mmol), followed bySP-1B-2 using chloroacetone (d2) (2.6 eq.; preparative TLC, eluent3—3:1;followed by a second chromatography with eluent1—70:60:15). ¹H NMR (300MHz, CDCl₃): δ=2.12 (3H, d, Me), 2.19 (3H, s, Me), 6.26 (1H, s, Ar—H),7.11 (1H, s, Ar—H), 7.23 (1H, d, Ar—H), 7.36 (1H, t, Ar—H), 7.38 (1H, d,Ar—H), 7.43 (1H, m, Ar—H), 7.44 (1H, td, Ar—H), 7.49 (1H, s, Ar—H);[M+H]⁺ (HPLC/MS): 291.13.

Example 18: 3-methyl-5-(m-tolyl)-7H-furo[3,2-g]chromen-7-one

This compound was synthesized from ethyl 3-oxo-3-m-tolylpropanoate andresorcinol in 40% yield according to SP-1A (0.72 mmol), followed bySP-1B-1 using chloroacetone (d2). ¹H NMR (300 MHz, CDCl₃): δ=2.17 (3H,d, Me), 2.47 (3H, s, Me), 6.31 (1H, s, Ar—H), 7.29 (1H, d, Ar—H), 7.30(1H, m, Ar—H), 7.36 (1H, d, Ar—H), 7.44 (1H, t, Ar—H), 7.45 (1H, m,Ar—H), 7.49 (1H, s, Ar—H), 7.54 (1H, s, Ar—H); [M+H]⁺ (HPLC/MS): 291.13.

Example 19: 5-(2-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one

This compound was synthesized from ethyl (2-methoxybenzoyl)acetate andresorcinol in 18% yield according to SP-1A (0.72 mmol), followed bySP-1B-1 using chloroacetone (d2) (2.6 eq.). ¹H NMR (300 MHz, CDCl₃):δ=2.11 (3H, d, Me), 3.73 (3H, s, OMe), 6.28 (1H, s, Ar—H), 7.06 (1H, d,Ar—H), 7.10 (1H, td, Ar—H), 7.22 (1H, s, Ar—H), 7.25 (1H, dd, Ar—H),7.40 (1H, m, Ar—H), 7.43 (1H, s, Ar—H), 7.49 (1H, td, Ar—H); [M+H]⁺(HPLC/MS): 307.07.

Example 20: 5-(3-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one

This compound was synthesized from ethyl (3-methoxybenzoyl)acetate andresorcinol in 29% yield according to SP-1A (0.70 mmol), followed bySP-1B-1 using chloroacetone (d2). ¹H NMR (300 MHz, CDCl₃): δ=2.18 (3H,d, Me), 3.88 (3H, s, OMe), 6.33 (1H, s, Ar—H), 7.02 (1H, s, Ar—H),7.05-7.13 (2H, m, Ar—H), 7.45 (1H, m, Ar—H), 7.45-7.52 (2H, m, Ar—H),7.56 (1H, s, Ar—H); [M+H]⁺ (HPLC/MS): 307.10.

Example 21: 5-(2-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one

Synthesized from ethyl (2-chlorobenzoyl)acetate and resorcinol in 52%yield according to SP-LA (0.66 mmol), followed by SP-1B-2 usingchloroacetone (d2) (preparative TLC, eluent1—70:60:15). ¹H NMR (300 MHz,CDCl₃): δ=2.14 (3H, d, Me), 6.31 (1H, s, Ar—H), 7.12 (1H, s, Ar—H), 7.36(1H, dd, Ar—H), 7.44 (1H, m, Ar—H), 7.45 (1H, td, Ar—H), 7.49 (1H, s,Ar—H), 7.50 (1H, td, Ar—H), 7.59 (1H, dd, Ar—H); [M+H]⁺ (HPLC/MS):311.03.

Example 22: 5-(3-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one

This compound was synthesized from ethyl (3-chlorobenzoyl)acetate andresorcinol in 43% yield according to SP-1A (0.68 mmol), followed bySP-1B-1 using chloroacetone (d2). ¹H NMR (300 MHz, CDCl₃): δ=2.19 (3H,d, Me), 6.31 (1H, s, Ar—H), 7.38 (1H, d, Ar—H), 7.42-7.58 (6H, m, Ar—H);[M+H]⁺ (HPLC/MS): 311.09.

Example 23: 9-methoxy-3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one

This compound was synthesized from ethyl benzoylacetate and2-methoxyresorcinol in 17% yield according to SP-1A (0.57 mmol),followed by SP-1B-2 using chloroacetone (d2) (preparative TLC,eluent1—10:6:1). ¹H NMR (300 MHz, CDCl₃): δ=2.15 (3H, d, Me), 4.32 (3H,s, OMe), 6.32 (1H, s, Ar—H), 7.19 (1H, s, Ar—H), 7.45 (1H, m, Ar—H),7.47-7.58 (5H, m, Ar—H); [M+H]⁺ (HPLC/MS): 307.07.

Example 24: 3-methyl-5-phenyl-7H-furo[2,3-b]pyrano[3,2-e]pyridin-7-one(cf. Scheme 6)

The reaction was performed according to SP-3A (1^(st) step) using ethylbenzoylacetate (b4) and pyridine-2,6-diol hydrochloride (r2) (6.78mmol). In addition, NEt₃ (1.2 eq.) was added. As this reaction stepdirectly yielded the cyclized intermediate, the treatment with TFA wasomitted (SP-3A, 2^(nd) step). The solvent was decanted from theprecipitated product, which was washed with petroleum ether and purifiedby preparative TLC (eluent2 —9:1) to give7-hydroxy-4-phenyl-2H-pyrano[2,3-b]pyridin-2-one (s). This intermediatewas converted into7-(2-oxopropoxy)-4-phenyl-2H-pyrano[2,3-b]pyridin-2-one according toSP-1B-2 to give the title compound in an overall yield of 2%: 1^(st)step, using 2.6 eq. chloroacetone (d2) (reaction time: 3 h). Thefiltrate upon removal of the salts was purified by preparative TLC(eluent2—95:5), followed by preparative TLC (CH₂Cl₂/MeOH/NEt₃ —96:2:2).

Intermediate 7-(2-oxopropoxy)-4-phenyl-2H-pyrano[2,3-b]pyridin-2-one: ¹HNMR (300 MHz, CDCl₃): δ=2.27 (3H, s, Me), 5.05 (2H, s, CH₂), 6.29 (1H,s, Ar—H), 6.81 (1H, d, Ar—H), 7.39-7.43 (2H, m, Ar—H), 7.50-7.55 (3H, m,Ar—H), 7.80 (1H, d, Ar—H).

Title Compound: ¹H NMR (300 MHz, CDCl₃): δ=2.20 (3H, d, Me), 6.40 (1H,s, Ar—H), 7.46-7.50 (2H, m, Ar—H), 7.52 (1H, m, Ar—H), 7.56-7.61 (3H, m,Ar—H), 7.95 (1H, s, Ar—H); [M+H]⁺ (HPLC/MS): 277.91.

Example 25:3,6-dimethyl-5-phenyl-7H-furo[2,3-b]pyrano[3,2-e]pyridin-7-one (cfScheme 6)

This compound was synthesized in analogy to Example 24, using theappropriate β-ketoester ethyl 2-methyl-3-oxo-3-phenyl-propanoate (b4)and pyridine-2,6-diol hydrochloride (r2) in the first reaction step(heating was extended to 12 h). Overall yield: 3%.

Intermediate3-methyl-7-(2-oxopropoxy)-4-phenyl-2H-pyrano[2,3-b]pyridin-2-one: ¹H NMR(300 MHz, CDCl₃): δ=1.96 (3H, s, Me), 2.25 (3H, s, Me), 5.02 (2H, s,CH₂), 6.71 (1H, d, Ar—H), 7.18-7.22 (2H, m, Ar—H), 7.32 (1H, d, Ar—H),7.45-7.57 (3H, m, Ar—H).

Title compound: ¹H NMR (300 MHz, CDCl₃): δ=2.01 (3H, s, Me), 2.13 (3H,d, Me), 7.26-7.30 (2H, m, Ar—H), 7.46-7.48 (2H, m, Ar—H), 7.52-7.63 (3H,m, Ar—H); [M+H]⁺ (HPLC/MS): 291.83.

Example 26: 6-bromo-3,9-dimethyl-5-phenylfuro[3,2-g]quinolin-7(8H)-one

Synthesized from ethyl 3-oxo-3-phenylpropanoate and 3-amino-ortho-cresolaccording to SP-2 (3.0 mmol; SP-2A-1; workup SP-2B by columnchromatography, eluent2—95:5; workup SP-2C, 1^(st) step by preparativeTLC, eluent1—4:10:1) in 4% overall yield, along with3,9-dimethyl-5-phenylfuro[3,2-g]quinolin-7(8H)-one in 8% overall yield.

Intermediate 7-hydroxy-8-methyl-4-phenyl-1,2-dihydroquinolin-2-one (l1,Scheme 3): ¹H NMR (300 MHz, CDCl₃/CD₃OD; calibrated for residual signalsof CD₃OD): δ=2.32 (3H, s, Me), 6.38 (1H, s, Ar—H), 6.71 (1H, d, Ar—H),7.21 (1H, d, Ar—H), 7.35-7.40 (2H, m, Ar—H), 7.42-7.49 (3H, m, Ar—H); ¹HNMR (300 MHz, d₆-acetone): δ=2.42 (3H, s, Me), 6.26 (1H, s, Ar—H), 6.79(1H, d, Ar—H), 7.16 (1H, d, Ar—H), 7.42-7.47 (2H, m, Ar—H), 7.48-7.56(3H, m, Ar—H).

Intermediate3,6-dibromo-7-hydroxy-8-methyl-4-phenyl-1,2-dihydroquinolin-2-one (m1,Scheme 3): ¹H NMR (300 MHz, CDCl₃): δ=2.46 (3H, s, Me), 6.08 (1H, br s,OH), 7.09 (1H, s, Ar—H), 7.22-7.26 (2H, m, Ar—H), 7.49-7.59 (3H, m,Ar—H), 9.53 (1H, br s, NH).

By-product 3,9-dimethyl-5-phenylfuro[3,2-g]quinolin-7(8H)-one (n1, R²═H,Scheme 3): ¹H NMR (300 MHz, CDCl₃/CD₃OD 10:1; calibrated for residualsignal of CDCl₃): δ=2.14 (3H, d, Me), 2.67 (3H, s, Me), 6.62 (1H, s,Ar—H), 7.26 (1H, s, Ar—H), 7.44-7.54 (6H, m, Ar—H).

Title compound (n1, R²═Br, Scheme 3): ¹H NMR (300 MHz, CDCl₃): δ=2.09(3H, d, Me), 2.62 (3H, s, Me), 7.05 (1H, s, Ar—H), 7.28-7.33 (2H, m,Ar—H), 7.41 (1H, m, Ar—H), 7.51-7.62 (3H, m, Ar—H), 9.10 (1H, br s, NH);[M+H]⁺ (HPLC/MS): 367.92.

Alternatively, the title compound was synthesized from ethyl3-oxo-3-phenylpropanoate and 3-amino-ortho-cresol according to SP-3(16.0 mmol; workup SP-3A, 2nd step by washing the resulting crude solidwith CH₂Cl₂; SP-3B performed to yield double-bromination; workup SP-3C,2^(nd) step by preparative TLC, petroleum ether/CH₂Cl₂/ethylacetate—2:5:3) in 2% overall yield (cf. Scheme 4).

Example 27:6-bromo-5-(2-fluorophenyl)-3,9-dimethylfuro[3,2-g]quinolin-7(8H)-one

The title compound was synthesized from ethyl (2-fluorobenzoyl)acetateand 3-amino-ortho-cresol according to SP-2 (2.0 mmol; SP-2A-2; workupSP-2B by preparative TLC, eluent1—4:6:1; workup SP-2C, 1^(st) step bypreparative TLC, eluent3—1:1) in 0.5% overall yield along with5-(2-fluorophenyl)-3,9-dimethylfuro[3,2-g]quinolin-7(8H)-one in 1%overall yield.

Intermediate4-(2-fluorophenyl)-7-hydroxy-8-methyl-1,2-dihydroquinolin-2-one (l1,Scheme 3): ¹H NMR (300 MHz, CD₃OD): δ=2.34 (3H, s, Me), 6.34 (1H, s,Ar—H), 6.73 (1H, d, Ar—H), 6.97 (1H, dd, Ar—H), 7.22-7.40 (3H, m, Ar—H),7.49-7.56 (1H, m, Ar—H).

Intermediate3,6-dibromo-4-(2-fluorophenyl)-7-hydroxy-8-methyl-1,2-dihydroquinolin-2-one(m1, Scheme 3): ¹H NMR (300 MHz, CDCl₃): δ=2.43 (3H, s, Me), 7.07 (1H,s, Ar—H), 7.19-7.40 (4H, m, Ar—H and OH), 7.50-7.58 (1H, m, Ar—H), 9.19(1H, br s, NH).

Intermediate3,6-dibromo-4-(2-fluorophenyl)-8-methyl-7-(2-oxopropoxy)-1,2-dihydroquinolin-2-one:¹H NMR (300 MHz, CDCl₃): δ=2.38 (3H, s, Me), 2.56 (3H, s, Me), 4.51 (2H,s, CH₂), 7.17 (1H, s, Ar—H), 7.20-7.39 (3H, m, Ar—H), 7.52-7.60 (1H, m,Ar—H), 10.16 (1H, br s, NH).

By-product 5-(2-fluorophenyl)-3,9-dimethylfuro[3,2-g]quinolin-7(8H)-one(n1, R²═H, Scheme 3): Result of LC/MS [M+H]+: 307.92

Title Compound (n1, R²═Br, Scheme 3): ¹H NMR (300 MHz, CDCl₃): δ=2.11(3H, d, Me), 2.61 (3H, s, Me), 7.03 (1H, s, Ar—H), 7.27-7.33 (2H, m,Ar—H), 7.37 (1H, td, Ar—H), 7.43 (1H, m, Ar—H), 7.55 (1H, m, Ar—H), 8.98(1H, br s, NH); [M+H]⁺ (HPLC/MS): 385.72.

Example 28:6-bromo-3,9-dimethyl-5-(o-tolyl)furo[3,2-g]quinolin-7(8H)-one Example29: 3,9-dimethyl-5-(o-tolyl)furo[3,2-g]quinolin-7(8H)-one

The title compounds (Examples 28 and 29) were synthesized from ethyl3-oxo-3-o-tolylpropanoate and 3-amino-ortho-cresol according to SP-2(2.0 mmol; SP-2A-2; workup SP-2B by preparative TLC, eluent1—4:6:1;workup SP-2C, 1^(st) step by preparative TLC, eluent3—1:1) in 1% overallyield for 6-bromo-3,9-dimethyl-5-(o-tolyl)furo[3,2-g]quinolin-7(8H)-onealong with 3,9-dimethyl-5-(o-tolyl)furo[3,2-g]quinolin-7(8H)-one in 0.5%overall yield.

Intermediate7-hydroxy-8-methyl-4-(2-methylphenyl)-1,2-dihydroquinolin-2-one (l1,Scheme 3): ¹H NMR (300 MHz, CD₃OD): δ=2.08 (3H, s, Me), 2.34 (3H, s,Me), 6.23 (1H, s, Ar—H), 6.68 (1H, d, Ar—H), 6.79 (1H, d, Ar—H), 7.15(1H, d, Ar—H), 7.26-7.40 (3H, m, Ar—H).

Intermediate3,6-dibromo-7-hydroxy-8-methyl-4-(2-methylphenyl)-1,2-dihydroquinolin-2-one(m1, Scheme 3): ¹H NMR (300 MHz, CDCl₃): δ=2.07 (3H, s, Me), 2.44 (3H,s, Me), 6.96 (1H, s, Ar—H), 7.06 (1H, d, Ar—H), 7.31-7.46 (4H, m, Ar—Hand OH), 9.24 (1H, br s, NH).

Intermediate3,6-dibromo-8-methyl-4-(2-methylphenyl)-7-(2-oxopropoxy)-1,2-dihydroquinolin-2-one:¹H NMR (300 MHz, CDCl₃): δ=2.07 (3H, s, Me), 2.38 (3H, s, Me), 2.56 (3H,s, Me), 4.50 (2H, s, CH₂), 7.05 (1H, s, Ar—H), 7.06 (1H, d, Ar—H),7.33-7.47 (3H, m, Ar—H), 10.07 (1H, br s, NH).

Title Compound, Example 28: ¹H NMR (300 MHz, CDCl₃): δ=2.08 (3H, d, Me),2.09 (3H, s, Me), 2.62 (3H, s, Me), 6.93 (1H, s, Ar—H), 7.12 (1H, d,Ar—H), 7.35-7.48 (4H, m, Ar—H), 9.08 (1H, br s, NH); [M+H]⁺ (HPLC/MS):381.75.

Title Compound, Example 29: ¹H NMR (300 MHz, CDCl₃): δ=2.11 (3H, d, Me),2.14 (3H, s, Me), 2.61 (3H, s, Me), 6.49 (1H, s, Ar—H), 7.05 (1H, s,Ar—H), 7.26-7.45 (5H, m, Ar—H), 8.99 (1H, br s, NH); [M+H]⁺ (HPLC/MS):303.92.

Example 30:5-(2-fluorophenyl)-3,6,9-trimethylfuro[3,2-g]quinolin-7(8H)-one

The title compound was synthesized from ethyl3-(2-fluorophenyl)-2-methyl-3-oxopropanoate and 3-amino-o-cresol (8.0mmol) according to SP-3A (column chromatography, eluent2—95:5), SP-3Band SP-2C (purification by preparative TLC, eluent2—95:5, followed bypreparative TLC, eluent2—95:5 followed by preparative HPLC) in anoverall yield of 4%. ¹H NMR (300 MHz, d6-DMSO): δ=1.86 (3H, s, Me), 2.02(3H, d, Me), 2.60 (3H, s, Me), 6.84 (1H, s, Ar—H), 7.37 (1H, td, Ar—H),7.41-7.49 (2H, m, Ar—H), 7.62 (1H, m, Ar—H), 7.75 (1H, m, Ar—H), 11.13(1H, br s, NH); [M+H]⁺ (HPLC/MS): 322.05.

Example 31: 3,6,9-trimethyl-5-phenylfuro[3,2-g]quinolin-7(8H)-one

The title compound was synthesized from 3-amino-o-cresol (6.5 mmol) andethyl 2-methyl-3-oxo-3-phenyl-propanoate according to SP-3 (SP-3A:column chromatography, eluent2—95:5; SP-3C, 2^(nd) step: preparativeTLC, eluent2—95:5) in an overall yield of 10%.

Intermediate 7-hydroxy-3,8-dimethyl-4-phenyl-1,2-dihydroquinolin-2-one(12, Scheme 4): ¹H NMR (300 MHz, d6-DMSO): δ=1.78 (3H, s, Me), 2.25 (3H,s, Me), 6.56 (1H, d, Ar—H), 6.62 (1H, d, Ar—H), 7.19-7.23 (2H, m, Ar—H),7.43-7.56 (3H, m, Ar—H), 9.82 (1H, br s, NH or OH), 10.68 (1H, br s, OHor NH).

Title Compound: ¹H NMR (300 MHz, d6-DMSO): δ=1.83 (3H, s, Me), 2.00 (3H,d, Me), 2.59 (3H, s, Me), 6.84 (1H, s, Ar—H), 7.29 (2H, m, Ar—H),7.49-7.62 (3H, m, Ar—H), 7.73 (1H, m, Ar—H), 11.03 (1H, br s, NH);[M+H]⁺ (HPLC/MS): 304.18.

Alternatively,6-bromo-7-hydroxy-3,8-dimethyl-4-phenyl-1,2-dihydroquinolin-2-oneresulting from step SP-3B can be converted into the title compoundaccording to SP-2C (product was repeatedly crystallized from MeOH,mother liquor was purified by preparative TLC, eluent3—9:1) in anoverall yield of 6% based on 3-amino-o-cresol (cf. Scheme 4).

Example 32: 3,8,9-trimethyl-5-phenylfuro[3,2-g]quinolin-7(8H)-one

The title compound was synthesized from3,9-dimethyl-5-phenylfuro[3,2-g]quinolin-7(8H)-one (by-product of thesynthesis of Example 26; 0.1 mmol) according to SP-4 in 11% yield alongwith 45% by-product 7-methoxy-3,9-dimethyl-5-phenylfuro[3,2-g]quinoline.

Title Compound (n2, R²═H, Scheme 3): ¹H NMR (300 MHz, CDCl₃): δ=2.13(3H, d, Me), 2.85 (3H, s, Me), 3.92 (3H, s, NMe), 6.57 (1H, s, Ar—H),7.42-7.53 (7H, m, Ar—H); [M+H]⁺ (HPLC/MS): 304.16.

Lactim ether by-product7-methoxy-3,9-dimethyl-5-phenylfuro[3,2-g]quinoline (o, R²═H, Scheme 3):¹H NMR (300 MHz, CDCl₃): δ=2.20 (3H, d, Me), 2.90 (3H, s, Me), 4.15 (3H,s, OMe), 6.81 (1H, s, Ar—H), 7.46-7.55 (6H, m, Ar—H), 7.66 (1H, m,Ar—H).

Example 33:6-bromo-3,8,9-trimethyl-5-phenylfuro[3,2-g]quinolin-7(8H)-one

The title compound was synthesized from Example 26 (0.1 mmol) accordingto SP-4 in 3% yield with 33% by-product6-bromo-7-methoxy-3,9-dimethyl-5-phenylfuro[3,2-g]quinoline.

Title Compound (n2, R²═Br, Scheme 3): ¹H NMR (300 MHz, CDCl₃): δ=2.08(3H, d, Me), 2.84 (3H, s, Me), 4.00 (3H, s, NMe), 7.05 (1H, s, Ar—H),7.26-7.31 (2H, m, Ar—H), 7.41 (1H, m, Ar—H), 7.51-7.60 (3H, m, Ar—H);[M+H]⁺ (HPLC/MS): 381.80.

Lactim ether by-product6-bromo-7-methoxy-3,9-dimethyl-5-phenylfuro[3,2-g]quinoline (o, R²═Br,Scheme 3): ¹H NMR (300 MHz, CDCl₃): δ=2.13 (3H, d, Me), 2.89 (3H, s,Me), 4.23 (3H, s, OMe), 7.20 (1H, s, Ar—H), 7.29-7.34 (2H, m, Ar—H),7.47 (1H, m, Ar—H), 7.50-7.60 (3H, m, Ar—H).

Example 34: 3,6,8,9-tetramethyl-5-phenylfuro[3,2-g]quinolin-7(8H)-one

Synthesis of 2-methyl-3-(methylamino)phenol according to US2004/0127747,example 3 (cf. Scheme 4, conversion of k1 into k2): 3-amino-o-cresol(4.1 mmol, 1.0 eq.) and sodium Y Zeolite (125 mg/mmol; from SigmaAldrich, order no. 334448) were suspended in dimethyl carbonate (5mL/mmol). The resulting mixture was stirred at 90° C. for 48 h. Thereaction mixture was cooled to room temperature, filtered andconcentrated in vacuo. Crude product was used for further transformationwithout purification.

The title compound was synthesized from 2-methyl-3-(methylamino)phenol(6.5 mmol) and ethyl 2-methyl-3-oxo-3-phenyl-propanoate according toSP-3 (SP-3A: column chromatography, eluent2—95:5; SP-3C, 1^(st) step:reaction time 1 h, preparative TLC, eluent3—1:1; SP-3C, 2nd step:purification by preparative TLC, eluent3—1:1), overall yield 4%.

Intermediate6-bromo-1,3,8-trimethyl-4-phenyl-7-(prop-2-en-1-yloxy)-1,2-dihydroquinolin-2-one:¹H NMR (300 MHz, CDCl₃): δ=1.96 (3H, s, Me), 2.59 (3H, s, Me), 3.79 (3H,s, NMe), 4.50 (2H, dt, CH₂), 5.30 (1H, dq, alkenyl-CH₂), 5.45 (1H, dq,alkenyl-CH₂), 6.16 (1H, ddt, alkenyl-CH), 7.09 (1H, s, Ar—H), 7.14-7.19(2H, m, Ar—H), 7.42-7.54 (3H, m, Ar—H).

Title Compound: ¹H NMR (300 MHz, CDCl₃): δ=1.98 (3H, s, Me), 2.07 (3H,d, Me), 2.83 (3H, s, Me), 3.95 (3H, s, NMe), 6.98 (1H, s, Ar—H),7.21-7.25 (2H, m, Ar—H), 7.38 (1H, m, Ar—H), 7.44-7.55 (3H, m, Ar—H);[M+H]⁺ (HPLC/MS): 318.10.

Example 35: 3,6,9-trimethyl-5-phenyl-7H-chromeno[6,7-d]isoxazol-7-one

Starting material 7-hydroxy-3,8-dimethyl-4-phenyl-2H-chromen-2-one wassynthesized as described above (intermediate in the synthesis of Example9), 79% yield following SP-1A (4.0 to 8.0 mmol; crude product wasfiltered through silica gel pad, CH₂Cl₂ to eluent2—95:5).

7-hydroxy-3,8-dimethyl-4-phenyl-2H-chromen-2-one (1.88 mmol) wasbrominated according to SP-3B to give6-bromo-7-hydroxy-3,8-dimethyl-4-phenyl-2H-chromen-2-one in 64% yield(upon purification by preparative TLC, eluent CH₂Cl₂). ¹H NMR (300 MHz,CDCl₃): δ=1.95 (3H, s, Me), 2.43 (3H, s, Me), 5.87 (1H, br s, OH), 6.94(1H, s, Ar—H), 7.17-7.22 (2H, m, Ar—H), 7.46-7.57 (3H, m, Ar—H).

The title compound was synthesized from6-bromo-7-hydroxy-3,8-dimethyl-4-phenyl-2H-chromen-2-one (1.0 mmol)according to SP-5A and SP-5C (purification each by preparative TLC,eluent CH₂Cl₂) in an overall yield of 16% (cf. Scheme 5). ¹H NMR (300MHz, CDCl₃): =1.99 (3H, s, Me), 2.44 (3H, s, Me), 2.67 (3H, s, Me), 7.01(1H, s, Ar—H), 7.24-7.28 (2H, m, Ar—H), 7.50-7.61 (3H, m, Ar—H); [M+H]⁺(HPLC/MS): 306.09.

Example 36: 3,6,9-trimethyl-5-phenylisoxazolo[4,5-g]quinolin-7(8H)-one

The synthesis of6-bromo-7-hydroxy-3,8-dimethyl-4-phenylquinolin-2(1H)-one is describedas an intermediate in the synthesis of Example 31, resulting fromreaction SP-3A (20-70 mmol) and SP-3B (0.4-14 mmol) in 33% yield.

The title compound was synthesized from6-bromo-7-hydroxy-3,8-dimethyl-4-phenylquinolin-2(1H)-one (0.9 mmol)according to SP-5A and SP-5C (purification each by preparative TLC,eluent2—95:5) in an overall yield of 8%. ¹H NMR (300 MHz, d6-DMSO):=1.84 (3H, s, Me), 2.37 (3H, s, Me), 2.61 (3H, s, Me), 7.06 (1H, s,Ar—H), 7.28-7.33 (2H, m, Ar—H), 7.51-7.64 (3H, m, Ar—H), 11.24 (1H, brs, NH); [M+H]⁺ (HPLC/MS): 305.05.

Example 37: 6,9-dimethyl-4-phenyl-2H-thieno-[3,2-g]chromen-2-one (cf.Scheme 7)

The synthesis of the starting material7-hydroxy-8-methyl-4-phenyl-2H-chromen-2-one is described above as anintermediate in the synthesis of compound e1 in Scheme 2,3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one, which was obtained in75% yield from ethyl benzoylacetate and 2-methylresorcinol followingSP-1A (50 mmol).

7-hydroxy-8-methyl-4-phenyl-2H-chromen-2-one (c2) (2.0 mmol) wasdissolved in dioxane (5 mL/mmol), 4-dimethylaminopyridine (0.1 eq.),dimethylthiocarbamoyl chloride (1.2 eq.) and triethylamine (2.0 eq.)were added, and the mixture was stirred at 100° C. overnight. Thereaction mixture was cooled to room temperature and filtered. The filtercake was washed with dioxane and the filtrate was concentrated in vacuo.¹H NMR (300 MHz, CDCl₃): δ=2.34 (3H, s, Me), 3.40 and 3.48 (each 3H, s,NMe₂), 6.35 (1H, s, Ar—H), 6.93 (1H, d, Ar—H), 7.34 (1H, d, Ar—H),7.45-7.47 (2H, m, Ar—H), 7.50-7.53 (3H, m, Ar—H).

The resulting O-(8-methyl-2-oxo-4-phenyl-2H-chromen-7-yl)dimethylcarbamothioate (v) was dissolved in diphenyl ether (5 mL/mmol)and stirred at 250° C. under microwave irradiation for 2 h. The reactionmixture was directly loaded onto a flash chromatography column(petroleum ether to eluent3, 2:1) to giveS-(8-methyl-2-oxo-4-phenyl-2H-chromen-7-yl) dimethylcarbamothioate in83% yield over two steps. ¹H NMR (300 MHz, CDCl₃): δ=2.60 (3H, s, Me),3.09 (6H, br s, NMe₂), 6.39 (1H, s, Ar—H), 7.30 (1H, d, Ar—H), 7.38 (1H,d, Ar—H), 7.41-7.45 (2H, m, Ar—H), 7.49-7.53 (3H, m, Ar—H).

S-(8-methyl-2-oxo-4-phenyl-2H-chromen-7-yl) dimethylcarbamothioate wasdissolved in MeOH (20 mL/mmol). 2 M aq. NaOH (6 eq.) was added, and themixture was stirred under reflux overnight, followed by partitioningbetween water and CH₂Cl₂. The aqueous phase was then acidified with HCl.Extraction with Et₂O, drying of the organic phase over MgSO₄ and removalof solvent gave crude 7-mercapto-8-methyl-4-phenyl-2H-chromen-2-one (w).

7-mercapto-8-methyl-4-phenyl-2H-chromen-2-one (w) was converted into thetitle compound with chloroacetone (d2) (2.6 eq.) according to SP-1B-1.The product precipitated, was filtered off, taken up in CH₂Cl₂ andfiltered through a silica gel pad, eluent CH₂Cl₂. Yield over 3 steps(referring to S-(8-methyl-2-oxo-4-phenyl-2H-chromen-7-yl)dimethylcarbamothioate): 8%.

¹H NMR (300 MHz, CDCl₃): δ=2.32 (3H, d, Me), 2.70 (3H, s, Me), 6.37 (1H,s, Ar—H), 7.06 (1H, m, Ar—H), 7.52-7.58 (5H, m, Ar—H), 7.60 (1H, s,Ar—H); [M+H]⁺ (HPLC/MS): 306.85.

Example 38: 2,4-dimethyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one (cf.Scheme 7)

The synthesis of the starting material7-hydroxy-8-methyl-4-phenyl-2H-chromen-2-one is described above as anintermediate in the synthesis compound e1 in Scheme 2,3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one, which was obtained in75% yield from ethyl benzoylacetate and 2-methylresorcinol followingSP-1A (50 mmol).

7-hydroxy-8-methyl-4-phenyl-2H-chromen-2-one (c2) (4.8 mmol; 1.0 eq.)was dissolved in concentrated sulfuric acid (1.9 mL/mmol). Upon coolingto −20° C., a 1:3 (v/v) mixture of concentrated nitric acid andconcentrated sulfuric acid (0.3 mL/mmol) was added slowly over a periodof 30 min Stirring was continued at −20° C. for 10 min. The mixture waspoured onto ice. The resulting suspension (upon thawing of the ice) wasextracted with CH₂Cl₂, combined organic layers were dried over MgSO₄,and the crude product was purified by preparative TLC (eluent3—2:1) togive 7-hydroxy-8-methyl-6-nitro-4-phenyl-2H-chromen-2-one in 33% yield.¹H NMR (300 MHz, CDCl₃): δ=2.45 (3H, s, Me), 6.34 (1H, s, Ar—H),7.41-7.45 (2H, m, Ar—H), 7.56-7.59 (3H, m, Ar—H), 8.18 (1H, s, Ar—H),11.20 (1H, s, OH).

Reduction of the nitro group was achieved in an autoclave:7-hydroxy-8-methyl-6-nitro-4-phenyl-2H-chromen-2-one (1.5 mmol, 1.0 eq.)was dissolved in MeOH (7.5 mL/mmol). Pd/C (10% on carbon; 0.05 eq. Pd)was added and the mixture was stirred under an atmosphere of hydrogen (4bar) at room temperature for 90 min. The suspension was filtratedthrough a PTFE-syringe filter (pore size: 0.45 μm), and the filtrate wasconcentrated and dried in high vacuum to give crude6-amino-7-hydroxy-8-methyl-4-phenyl-2H-chromen-2-one (y) in 88% yield.¹H NMR (300 MHz, CDCl₃): δ=2.29 (3H, s, Me), 4.42 (3H, br s, OH/NH₂),6.09 (1H, s, Ar—H), 6.60 (1H, s, Ar—H), 7.31-7.36 (2H, m, Ar—H),7.39-7.43 (3H, m, Ar—H).

Crude 6-amino-7-hydroxy-8-methyl-4-phenyl-2H-chromen-2-one (y) (1.2mmol, 1.0 eq.) was dissolved in DMF (2.5 mL/mmol), and pyridiniump-toluenesulfonate (0.15 eq.) and 1,1,1-trimethoxyethane (1.7 eq.) wereadded. The mixture was stirred at 60° C. for 90 min Volatiles wereremoved under reduced pressure and the residue was dried in high vacuum.The title compound 2,4-dimethyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one(z) was obtained in 15% upon purified via preparative TLC (eluent3—4:1).¹H NMR (300 MHz, CDCl₃): δ=2.64 (3H, s, Me), 2.66 (3H, s, Me), 6.36 (1H,s, Ar—H), 7.44-7.47 (2H, m, Ar—H), 7.51-7.54 (3H, m, Ar—H), 7.57 (1H, s,Ar—H); [M+H]⁺ (HPLC/MS): 291.83.

Example 39:4-methyl-2-((methylamino)methyl)-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one

Crude 6-amino-7-hydroxy-8-methyl-4-phenyl-2H-chromen-2-one wassynthesized as described in Example 38. Cyclization to give2-(bromomethyl)-4-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one wasperformed in analogy to Tetrahedron 2010, 66, 8189: To a mixture of6-amino-7-hydroxy-8-methyl-4-phenyl-2H-chromen-2-one (1.0 mmol, 1.0 eq.)in polyphosphoric acid (40 eq.) was added bromoacetic acid (1.15 eq.).The mixture was stirred at 130° C. overnight. Upon addition of water (40ml), the slurry was stirred at 60° C. for 30 min and cooled to roomtemperature again. The mixture was extracted with CH₂Cl₂, combinedorganic layers were washed with water and dried over MgSO₄, filtered andconcentrated in vacuo to give crude2-(bromomethyl)-4-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one in 50%yield. ¹H NMR (300 MHz, CDCl₃): δ=2.67 (3H, s, Me), 4.58 (2H, s, CH₂),6.39 (1H, s, Ar—H), 7.43-7.47 (2H, m, Ar—H), 7.50-7.55 (3H, m, Ar—H),7.66 (1H, s, Ar—H).

2-(bromomethyl)-4-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one (0.3mmol, 1.0 eq.) and potassium iodide (0.1 eq.) were suspended in THF (2mL/mmol). Upon addition of methylamine (2 M in THF; 1.2 eq.), themixture was stirred at 65° C. for 90 min. Upon cooling, the mixture waspartitioned between EtOAc and 2 N aq. NaOH. Combined organic phases werewashed with water, dried over MgSO₄ and concentrated in vacuo. The crudeproduct was purified by repeated preparative TLC (first, eluent2—95:5;second, eluent3—1:2) to give the title compound in 4% yield. ¹H NMR (300MHz, CDCl₃): δ=2.65 (3H, s, NMe), 2.67 (3H, s, Me), 4.20 (2H, s, CH₂),6.38 (1H, s, Ar—H), 7.43-7.47 (2H, m, Ar—H), 7.51-7.54 (3H, m, Ar—H),7.64 (1H, s, Ar—H); [M+H]⁺ (HPLC/MS): 321.17.

Example 40:5-(2-chlorophenyl)-3,6,9-trimethylfuro[3,2-g]quinolin-7(8H)-one

The title compound was synthesized from methyl3-(2-chlorophenyl)-2-methyl-3-oxopropanoate and 3-amino-o-cresol (8.1mmol) according to SP-3A (column chromatography, eluent2—95:5), SP-3Band SP-2C (purification by preparative TLC, 1^(st) step: eluent2—95:5;2^(nd) step: eluent2—95:5 followed by prep. HPLC) in an overall yield of4%. ¹H NMR (300 MHz, d6-DMSO): δ=1.80 (3H, s, Me), 2.01 (3H, d, Me),2.60 (3H, s, Me), 6.70 (1H, s, Ar—H), 7.37 (1H, m, Ar—H), 7.57 (2H, m,Ar—H), 7.69-7.73 (1H, m, Ar—H), 7.74 (1H, m, Ar—H), 11.12 (1H, br s,NH); [M+H]⁺ (HPLC/MS): 338.02.

Example 41: 3-cyclopropyl-9-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one

The synthesis of the starting material7-hydroxy-8-methyl-4-phenyl-2H-chromen-2-one is described above as anintermediate in the synthesis of compound e1 in Scheme 2, which wasobtained in 75% yield from ethyl benzoylacetate and 2-methylresorcinolfollowing SP-1A (50 mmol).

Starting with 7-hydroxy-8-methyl-4-phenyl-2H-chromen-2-one (0.4 mmol),the title compound was synthesized in 34% yield following SP-1B-2 using2.6 eq. 2-bromo-1-cyclopropylethanone (reaction time: 3 h) (uponextraction the final product was crystallized from methanol). ¹H NMR(300 MHz, CDCl₃): δ=0.60 (2H, m, CH₂), 0.87 (2H, m, CH₂), 1.71 (1H,m_(C), CH), 2.61 (3H, s, Me), 6.31 (1H, s, Ar—H), 7.35 (1H, s, Ar—H),7.48-7.57 (6H, m, Ar—H); [M+H]⁺ (HPLC/MS): 317.05.

Example 42:3-cyclopropyl-6,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one

This compound was synthesized from ethyl2-methyl-3-oxo-3-phenyl-propanoate and 2-methylresorcinol in 12% yieldaccording to SP-1A (4.2 mmol; crude product was filtered through a padof silica gel, CH₂Cl₂ to eluent2—95:5), followed by SP-1B-2 using2-bromo-1-cyclopropylethanone (2.6 eq.; reaction time step 1=75 min;reaction time step 2=45 min) (preparative TLC, eluent1—7:3:0.1). ¹H NMR(300 MHz, CDCl₃): δ=0.54 (2H, m, CH₂), 0.81 (2H, m, CH₂), 1.63 (1H,m_(C), CH), 1.99 (3H, s, Me), 2.61 (3H, s, Me), 7.01 (1H, s, Ar—H),7.26-7.31 (3H, m, Ar—H), 7.48-7.60 (3H, m, Ar—H); [M+H]⁺ (HPLC/MS):331.03.

Example 43: 3,6,9-trimethyl-4-phenyl-2H-thieno[3,2-g]chromen-2-one

Starting material 7-hydroxy-3,8-dimethyl-4-phenyl-2H-chromen-2-one wassynthesized as described above (intermediate in synthesis of Example 9)with a yield of 79% following SP-LA (4.0 to 8.0 mmol; crude product wasfiltered through a silica gel pad, CH₂Cl₂ to eluent2—95:5). ¹H NMR (300MHz, CDCl₃): δ=1.95 (3H, s, Me), 2.37 (3H, s, Me), 6.67 (1H, d, Ar—H),6.73 (1H, d, Ar—H), 7.18-7.23 (2H, m, Ar—H), 7.42-7.55 (3H, m, Ar—H).

Further transformations to give the title compound in analogy to Example37, starting with 4.0 mmol7-hydroxy-3,8-dimethyl-4-phenyl-2H-chromen-2-one (c2, cf. Scheme 7):

-   -   step1: additional preparative TLC (eluent2—95:5),        O-(3,8-dimethyl-2-oxo-4-phenyl-2H-chromen-7-yl)        dimethylcarbamothioate (v) in 63% yield; ¹H NMR (300 MHz,        CDCl₃): δ=2.02 (3H, s, Me), 2.37 (3H, s, Me), 3.43 and 3.49        (each 3H, s, NMe₂), 6.87 (1H, d, Ar—H), 6.91 (1H, d, Ar—H),        7.24-7.29 (2H, m, Ar—H), 7.47-7.58 (3H, m, Ar—H).    -   step2: S-(3,8-dimethyl-2-oxo-4-phenyl-2H-chromen-7-yl)        dimethylcarbamothioate in 85% yield; ¹H NMR (300 MHz, CDCl₃):        δ=2.00 (3H, s, Me), 2.59 (3H, s, Me), 3.08 (6H, br s, NMe₂),        6.83 (1H, d, Ar—H), 7.19-7.29 (3H, m, Ar—H), 7.47-7.55 (3H, m,        Ar—H).    -   step3: additional preparative TLC (eluent2—98:2),        7-mercapto-3,8-dimethyl-4-phenyl-2H-chromen-2-one (w) in 42%        yield.    -   step4: Conversion of        7-mercapto-3,8-dimethyl-4-phenyl-2H-chromen-2-one into the title        compound was achieved using chloroacetone (d2) (2.6 eq.)        according to SP-1B-1. Product precipitated, was filtered off,        purified by preparative TLC (eluent1—4:6:0.1). Yield: 10%.

Intermediate3,8-dimethyl-7-[2-oxopropyl)sulfanyl]-4-phenyl-2H-chromen-2-one: ¹H NMR(300 MHz, CDCl₃): δ=1.95 (3H, s, Me), 2.25 (3H, s, Me), 2.51 (3H, s,Me), 3.69 (2H, s, CH₂), 6.76 (1H, d, Ar—H), 6.96 (1H, d, Ar—H),7.16-7.20 (2H, m, Ar—H), 7.42-7.53 (3H, m, Ar—H).

Title Compound: ¹H NMR (300 MHz, CDCl₃): δ=2.01 (3H, s, Me), 2.23 (3H,d, Me), 2.68 (3H, s, Me), 7.01 (1H, m, Ar—H), 7.11 (1H, s, Ar—H),7.26-7.30 (2H, m, Ar—H), 7.49-7.60 (3H, m, Ar—H); [M+H]⁺ (HPLC/MS):321.06.

Example 44: 3,9-dimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one

This compound was synthesized from methyl3-oxo-3-(pyridin-3-yl)propanoate and 2-methylresorcinol in 16% yieldaccording to SP-1A (0.64 mmol), followed by SP-1B-2 using chloroacetone(d2) (preparative TLC, eluent1—10:6:1). ¹H NMR (300 MHz, CDCl₃): δ=2.15(3H, d, Me), 2.61 (3H, s, Me), 6.30 (1H, s, Ar—H), 7.24 (1H, s, Ar—H),7.46 (1H, m, Ar—H), 7.52 (1H, ddd, Ar—H), 7.83 (1H, dt, Ar—H), 8.76 (1H,d, Ar—H), 8.80 (1H, dd, Ar—H); [M+H]⁺ (HPLC/MS): 292.04.

Example 45:3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile

3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one (Example 9, 8.0mmol) was 2-brominated according to the bromination protocol describedfor Scheme 2 (conversion of e2 into f2), yielding 98% of2-bromo-3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one afterpurification by preparative TLC (eluent2—99:1). The latter (0.39 mmol)was converted into the title compound according to the proceduredescribed for Example 13 (purification by subsequent preparative TLCs,eluent 2—98:2, then eluent3—9:1) in 6% yield. ¹H NMR (300 MHz, CDCl₃):δ=1.99 (3H, s, Me), 2.30 (3H, s, Me), 2.63 (3H, s, Me), 6.98 (1H, s,Ar—H), 7.23-7.27 (2H, m, Ar—H), 7.51-7.60 (3H, m, Ar—H); [M+H]⁺(HPLC/MS): 330.05.

Example 46:2-((dimethylamino)methyl)-3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one (Example 9, 2.3mmol) was 2-chloromethylated according to the chloromethylation protocoldescribed for Scheme 2 (conversion of e2 into h2), yielding 73% of2-(chloromethyl)-3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-oneafter recrystallization of the precipitate from methanol. The latter(0.39 mmol) was converted into the title compound according to theprocedure described for Example 15 (purification by repeated preparativeTLC, eluent 2—95:5, then eluent3—9:1) in 18% yield. ¹H NMR (300 MHz,CDCl₃): δ=1.97 (3H, s, Me), 2.07 (3H, s, Me), 2.30 (6H, s, NMe₂), 2.62(3H, s, Me), 3.57 (2H, s, CH₂), 6.82 (1H, s, Ar—H), 7.23-7.28 (2H, m,Ar—H), 7.47-7.58 (3H, m, Ar—H); [M+H]⁺ (HPLC/MS): 361.97.

Example 47: 4-methyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one

6-amino-7-hydroxy-8-methyl-4-phenyl-2H-chromen-2-one was synthesized asdescribed for Example 38 (cf. Scheme 7). Cyclization to give the titlecompound was achieved in 33% yield:6-amino-7-hydroxy-8-methyl-4-phenyl-2H-chromen-2-one (y) (0.58 mmol; 1.0eq.) was dissolved in DMF (1.5 mL) and pyridinium p-toluenesulfonate(0.15 eq.) and trimethyl orthoformate (1.7 e.) were added. The mixturewas stirred at 60° C. for 90 min Volatiles were evaporated under reducedpressure, the residue was dried in vacuo and purified via consecutivepreparative TLCs (first: eluent2—95:5; second: eluent1—10:9:1). ¹H NMR(300 MHz, CDCl₃): δ=2.66 (3H, s, Me), 6.36 (1H, s, Ar—H), 7.42-7.48 (2H,m, Ar—H), 7.50-7.55 (3H, m, Ar—H), 7.71 (1H, s, Ar—H), 8.12 (1H, s,Ar—H); [M+H]⁺ (HPLC/MS): 278.05.

Example 48: 2,4,7-trimethyl-8-phenyl-6H-chromeno[6,7-d]oxazol-6-one

The synthesis of the starting material7-hydroxy-3,8-dimethyl-4-phenyl-2H-chromen-2-one is described above asan intermediate in the synthesis of Example 9, which was obtained in 79%yield following SP-1A (4.0 to 8.0 mmol; crude product was filteredthrough a pad of silica gel, CH₂Cl₂ to eluent2—95:5). Further steps wereperformed in analogy to the synthetic procedure described for Example 38(cf. Scheme 7):

-   a) 7-hydroxy-3,8-dimethyl-4-phenyl-2H-chromen-2-one (c2) (4.5 mmol)    was nitrosilated to give    7-hydroxy-3,8-dimethyl-6-nitro-4-phenyl-2H-chromen-2-one in 24%    yield;-   b) The 6-nitro group was reduced to give    6-amino-7-hydroxy-3,8-dimethyl-4-phenyl-2H-chromen-2-one (y) using    0.1 eq. [Pd], reaction time 16 h. Crude product was purified by    preparative TLC (eluent2—95:5); yield: 33%;-   c) Cyclization with 1,1,1-trimethoxyethane gave the title compound    in 23% yield. ¹H NMR (300 MHz, CDCl₃): δ=1.99 (3H, s, Me), 2.61 (3H,    s, Me), 2.62 (3H, s, Me), 7.06 (1H, s, Ar—H), 7.19-7.24 (2H, m,    Ar—H), 7.44-7.55 (3H, m, Ar—H); [M+H]⁺ (HPLC/MS): 306.06.

Example 49:3,6,8-trimethyl-5-phenylfuro[2,3-b][1,8]naphthyridin-7(8H)-one

To a solution of 2-methoxy-6-methylaminopyridine (20 mmol, 1.0 eq.) intetrahydrofuran (0.75 ml/mmol), N,N-diisopropylethylamine (1.5 eq.) wasadded at 0° C. To the reaction mixture a solution of propionyl chloride(1.5 eq.) in tetrahydrofuran (0.75 ml/mmol) was added dropwise over 20minutes. The mixture was stirred at r.t. for 1 h. The suspension wasfiltered and the solid was washed with tetrahydrofuran. The filtrate wasconcentrated under reduced pressure. The crude residue was partitionedbetween CH₂Cl₂ and saturated aq. NaHCO₃ solution, the aqueous phase wasextracted several times with CH₂Cl₂. The combined organic phases weredried over MgSO₄ and concentrated in vacuo. The crude residue waspurified by Kugelrohr (“ball tube”) vacuum distillation (boiling point:180° C. at 5 mbar) to give N-(6-methoxypyridin-2-yl)-N-methylpropanamideas a yellow oil in 88% yield; ¹H NMR (300 MHz, d6-DMSO): δ=0.99 (3H, t,CH₃), 2.33 (2H, q, CH₂), 3.24 (3H, s, NMe), 3.83 (3H, s, OMe), 6.71 (1H,d, Ar—H), 7.04 (1H, d, Ar—H), 7.77 (1H, t, Ar—H).

Lithiumdiisopropylamide solution (1.2 eq., 1.6 M in THF) in dry THF (1.5mL/mmol) was cooled to −15° C.,N-(6-methoxypyridin-2-yl)-N-methylpropanamide (15 mmol, 1.0 eq.) wasdissolved in dry THF (2 mL/mmol) and added dropwise within 3 minutesunder vigorous stirring in an inert atmosphere. The reaction mixture wasstirred for additional 60 minutes at −15° C. Ethylbenzoate (1.2 eq.) wasdissolved in THF (1.5 mL/mmol) and added dropwise within 15 minutes at−15° C. The mixture was allowed to warm to r.t. within 3 h and stirredat r.t. for additional 15 h, afterwards it was extracted with saturatedaq. NH₄Cl and brine, dried over Na₂SO₄ and concentrated in vacuo. Theresulting red-orange oil was crystallized from CH₂Cl₂/petroleum ether togive N-(6-methoxypyridin-2-yl)-N,2-dimethyl-3-oxo-3-phenylpropanamide asa pale yellow solid in 36% yield; ¹H NMR (300 MHz, CDCl₃): δ=1.45 (3H,d, Me), 3.33 (3H, s, NMe), 3.88 (3H, s, OMe), 4.63 (1H, q, CH), 6.62(1H, d, Ar—H), 6.78 (1H, d, Ar—H), 7.39 (2H, tt, Ar—H), 7.51 (1H, tt,Ar—H), 7.58 (1H, t, Ar—H), 7.86 (2H, dt, Ar—H).

N-(6-methoxypyridin-2-yl)-N,2-dimethyl-3-oxo-3-phenylpropanamide (5.2mmol) was cyclized in 86% to7-methoxy-1,3-dimethyl-4-phenyl-1,2-dihydro-1,8-naphthyridin-2-oneaccording to SP-3A, 2^(nd) step: reaction time 7 h; the reaction wasquenched by dropwise addition of the mixture onto iced water. Theresulting precipitated was filtered off, washed with aq. NaHCO₃(5%),taken up in CH₂Cl₂/MeOH 95:5 and filtered again. The filtrate was driedover Na₂SO₄ and concentrated in vacuo; ¹H NMR (300 MHz, CDCl₃): δ=2.01(3H, s, Me), 3.90 (3H, s, NMe), 4.04 (3H, s, OMe), 6.47 (1H, d, Ar—H),7.20 (2H, dt, Ar—H), 7.29 (1H, d, Ar—H), 7.40-7.54 (3H, m, Ar—H).

7-methoxy-1,3-dimethyl-4-phenyl-1,2-dihydro-1,8-naphthyridin-2-one (4.3mmol, 1.0 eq.) was suspended in aq. HBr (37%; 5 mL/mmol) and cooled to0° C. Bromine (1.1 eq.) was added dropwise. The reaction mixture wasstirred 30 min at 0° C. and 2 h at 100° C., then cooled to r.t. Theresulting precipitate was filtered off and washed with small quantitiesof MeOH to give6-bromo-7-hydroxy-1,3-dimethyl-4-phenyl-1,8-naphthyridin-2(1H)-one as apale orange solid in 93% yield; ¹H NMR (300 MHz, d6-DMSO): δ=1.85 (3H,s, Me), 3.70 (3H, s, NMe), 7.28 (1H, s, Ar—H), 7.29 (2H, dt, Ar—H),7.49-7.62 (3H, m, Ar—H).

6-bromo-7-hydroxy-1,3-dimethyl-4-phenyl-1,8-naphthyridin-2(1H)-one wasconverted into the title compound following SP-2C (3.5 mmol; 2^(nd)step: reaction time 2 h, final purification by column chromatography,CH₂Cl₂/ethyl acetate—7:3) in 51% yield. ¹H NMR (300 MHz, CDCl₃): δ=2.04(3H, s, Me), 2.12 (3H, m, Me), 3.97 (3H, s, NMe), 7.24-7.28 (2H, m,Ar—H), 7.41 (1H, m, Ar—H), 7.49 (1H, s, Ar—H), 7.48-7.59 (3H, m, Ar—H);[M+H]⁺ (HPLC/MS): 305.05.

Example 50: 3,9-dimethyl-5-phenyl-7H-chromeno[6,7-d]isoxazol-7-one

Starting material 7-hydroxy-8-methyl-4-phenyl-2H-chromen-2-one wassynthesized as described above (intermediate in the synthesis ofcompound e1, Scheme 2), obtained in 75% yield from ethyl benzoylacetateand 2-methylresorcinol following SP-1A (50 mmol).

Further transformation of 7-hydroxy-8-methyl-4-phenyl-2H-chromen-2-oneinto the title compound was achieved in 16% yield according to SP-5B(2.0 mmol; preparative TLC, eluent2—100:1) and SP-5C (preparative TLC,eluent2—95:5). ¹H NMR (300 MHz, CDCl₃): =2.51 (3H, s, Me), 2.67 (3H, s,Me), 6.35 (1H, s, Ar—H), 7.45-7.49 (2H, m, Ar—H), 7.51 (1H, s, Ar—H),7.54-7.59 (3H, m, Ar—H); [M+H]⁺ (HPLC/MS): 292.01.

Example 51: 3,9-dimethyl-5-phenylisoxazolo[4,5-g]quinolin-7(8H)-one

The synthesis of the starting material7-hydroxy-8-methyl-4-phenylquinolin-2(1H)-one was achieved in 57% yieldaccording SP-3A (16.2 mmol; final purification by washing the solid withCH₂Cl₂) starting from 3-amino-o-cresol and ethyl2-methyl-3-oxo-3-phenyl-propanoate.

Further transformation of 7-hydroxy-8-methyl-4-phenylquinolin-2(1H)-oneinto the title compound was achieved in 14% yield according to SP-5B(1.6 mmol; preparative TLC, eluent2—95:5) and SP-5C (preparative TLC,eluent2—95:5). ¹H NMR (300 MHz, CDCl₃): =2.51 (3H, s, Me), 2.72 (3H, s,Me), 6.64 (1H, s, Ar—H), 7.45-7.49 (2H, m, Ar—H), 7.53-7.60 (3H, m,Ar—H), 7.64 (1H, s, Ar—H), 10.01 (1H, br s, NH); [M+H]⁺ (HPLC/MS):291.06.

Example 52:3,6,8,9-tetramethyl-5-phenylisoxazolo[4,5-g]quinolin-7(8H)-one

Starting material 7-hydroxy-1,3,8-trimethyl-4-phenylquinolin-2(1H)-onewas synthesized as described above (intermediate in Example 34), 37%yield following SP-3A (4.37 mmol).

Further transformation of7-hydroxy-1,3,8-trimethyl-4-phenylquinolin-2(1H)-one into the titlecompound according to SP-5B, yield 25% (0.9 mmol; preparative TLC 1^(st)step eluent2—95:5; 2^(nd) step eluent3—1:1) and SP-5C (prep. HPLC). ¹HNMR (300 MHz, CDCl₃): δ=1.97 (3H, s, Me), 2.42 (3H, s, Me), 2.87 (3H, s,Me), 3.94 (3H, s, NMe), 7.10 (1H, s, Ar—H), 7.19-7.24 (2H, m, Ar—H),7.47-7.58 (3H, m, Ar—H); [M+H]⁺ (HPLC/MS): 318.94.

Example 53: 3,6,9-trimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one

This compound was synthesized from ethyl2-methyl-3-oxo-3-(pyridin-3-yl)propanoate and 2-methylresorcinol in 43%yield according to SP-1A (8.1 mmol; compound precipitated uponconcentration of organic phases from extraction), followed by SP-1B-2using 2.6 eq. chloroacetone (d2) (reaction time step 1=2 h, step 2=1 h;preparative TLC, eluent2—95:5, recrystallization from EtOH). ¹H NMR (300MHz, CDCl₃): δ=2.00 (3H, s, Me), 2.10 (3H, d, Me), 2.63 (3H, s, Me),6.79 (1H, s, Ar—H), 7.43 (1H, m, Ar—H), 7.54 (1H, ddd, Ar—H), 7.66 (1H,dt, Ar—H), 8.58 (1H, dd, Ar—H), 8.80 (1H, dd, Ar—H); [M+H]⁺ (HPLC/MS):306.00.

Example 54:3,6,9-trimethyl-5-(pyridin-3-yl)furo[3,2-g]quinolin-7(8H)-one

The building block7-hydroxy-3,8-dimethyl-4-(pyridin-3-yl)quinolin-2(1H)-one wassynthesized from ethyl 2-methyl-3-oxo-3-(pyridin-3-yl)propanoate and3-amino-o-cresol in 95% yield according to SP-3A (8.1 mmol); heating intrans-decalin resulted already in nearly complete cyclization of thelactam unit. To achieve complete conversion, heating in TFA was appliedaccording to SP-3A, 2nd step; upon removal of TFA, the oily residue wastaken up in CH₂Cl₂ and crushed out by addition of diethyl ether.

Bromination of 7-hydroxy-3,8-dimethyl-4-(pyridin-3-yl)quinolin-2(1H)-onewas achieved according to SP-3B in 65% yield (2.8 mmol): upon quenchingand diluting with water,6-bromo-7-hydroxy-3,8-dimethyl-4-(pyridin-3-yl)quinolin-2(1H)-oneprecipitated and was used as such after washing with small amounts ofMeOH and drying in vacuo.

6-bromo-7-hydroxy-3,8-dimethyl-4-(pyridin-3-yl)quinolin-2(1H)-one wasconverted into the title compound in 11% yield via SP-3C (0.72 mmol; 2ndstep: preparative TLC purification, eluent2—95:5). ¹H NMR (300 MHz,CDCl₃): δ=2.02 (3H, s, Me), 2.09 (3H, d, Me), 2.62 (3H, s, Me), 6.89(1H, s, Ar—H), 7.40 (1H, m, Ar—H), 7.53 (1H, ddd, Ar—H), 7.65 (1H, dt,Ar—H), 8.57 (1H, d, Ar—H), 8.79 (1H, dd, Ar—H), 9.20 (1H, br s, NH);[M+H]⁺ (HPLC/MS): 305.00.

Example 55:3,6,8,9-tetramethyl-5-(pyridin-3-yl)furo[3,2-g]quinolin-7(8H)-one

For the synthesis of building block 2-methyl-3-(methylamino)phenol, cf.Example 34.

The building block7-hydroxy-1,3,8-trimethyl-4-(pyridin-3-yl)quinolin-2(1H)-one wassynthesized from ethyl 2-methyl-3-oxo-3-(pyridin-3-yl)propanoate and2-methyl-3-(methylamino)phenol in 55% yield according to SP-3A (4.0mmol); heating in trans-decalin resulted already in (nearly) completecyclization of the lactam unit. If small quantities ofN-(3-hydroxy-2-methylphenyl)-N,2-dimethyl-3-oxo-3-(pyridin-3-yl)propanamidewere still present, these were converted into the desired product byheating in TFA according to SP-3A, 2^(nd) step; upon removal of TFA, theoily residue was taken up in CH₂Cl₂/MeOH 95:5 and crushed out byaddition of diethyl ether.

Bromination of7-hydroxy-1,3,8-trimethyl-4-(pyridin-3-yl)quinolin-2(1H)-one wasachieved according to SP-3B in 76% yield (1.7 mmol): upon quenching anddiluting with water,6-bromo-7-hydroxy-1,3,8-trimethyl-4-(pyridin-3-yl)quinolin-2(1H)-one wasextracted with ethyl acetate. This product was used as such withoutfurther purification steps.

6-bromo-7-hydroxy-1,3,8-trimethyl-4-(pyridin-3-yl)quinolin-2(1H)-one wasconverted into the title compound in 6% yield following SP-2C (0.70mmol; purification after 1^(st) step by preparative TLC, eluent2—95:5;final purification by preparative TLC, eluent2—95:5). ¹H NMR (300 MHz,CDCl₃): δ=1.99 (3H, s, Me), 2.08 (3H, d, Me), 2.84 (3H, s, Me), 3.95(3H, s, NMe), 6.85 (1H, s, Ar—H), 7.40 (1H, m, Ar—H), 7.55 (1H, ddd,Ar—H), 7.66 (1H, dt, Ar—H), 8.54 (1H, dd, Ar—H), 8.78 (1H, dd, Ar—H);[M+H]⁺ (HPLC/MS): 319.11.

Example 56:3,6,8,9-tetramethyl-5-(pyridin-3-yl)isoxazolo[4,5-g]quinolin-7(8H)-one

The synthesis of building block6-bromo-7-hydroxy-1,3,8-trimethyl-4-(pyridin-3-yl)quinolin-2(1H)-one isdescribed for Example 55.6-bromo-7-hydroxy-1,3,8-trimethyl-4-(pyridin-3-yl)quinolin-2(1H)-one wasconverted into the title compound in 8% yield following SP-5A (0.70mmol; preparative TLC purification, eluent2—95:5) and SP-5C (preparativeHPLC purification). ¹H NMR (300 MHz, CDCl₃): δ=1.99 (3H, s, Me), 2.44(3H, s, Me), 2.88 (3H, s, Me), 3.95 (3H, s, NMe), 6.97 (1H, s, Ar—H),7.59 (1H, dd, Ar—H), 7.68 (1H, dt, Ar—H), 8.55 (1H, s, Ar—H), 8.81 (1H,d, Ar—H); [M+H]⁺ (HPLC/MS): 320.01.

Example 57: 3,9-dimethyl-5-(pyridin-2-yl)-7H-furo[3,2-g]chromen-7-one

This compound was synthesized from methyl3-oxo-3-(pyridin-2-yl)propanoate and 2-methylresorcinol in 41% yieldaccording to SP-1A (0.41 mmol), followed by SP-1B-1 using chloroacetone(d2). ¹H NMR (300 MHz, CDCl₃): δ=2.15 (3H, d, Me), 2.61 (3H, s, Me),6.43 (1H, s, Ar—H), 7.44 (1H, m, Ar—H), 7.50 (1H, ddd, Ar—H), 7.53 (1H,s, Ar—H), 7.61 (1H, d, Ar—H), 7.94 (1H, td, Ar—H), 8.82 (1H, d, Ar—H);[M+H]⁺ (HPLC/MS): 292.06.

Example 58: 3,9-dimethyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one

This compound was synthesized from ethyl 3-oxo-3-(o-tolyl)propanoate and2-methylresorcinol in 7% yield according to SP-1A (4.0 mmol; preparativeTLC, eluent2—95:5), followed by SP-1B-2 using 2.6 eq. chloroacetone (d2)(reaction time step 1=1 h, step 2=1 h; preparative TLC, eluent2—95:5).¹H NMR (300 MHz, d6-DMSO): δ=2.06 (3H, d, Me), 2.13 (3H, s, Me), 2.55(3H, s, Me), 6.30 (1H, s, Ar—H), 6.93 (1H, s, Ar—H), 7.29 (1H, dd,Ar—H), 7.38 (1H, td, Ar—H), 7.42 (1H, dd, Ar—H), 7.45 (1H, td, Ar—H),7.88 (1H, d, Ar—H); [M+H]⁺ (HPLC/MS): 305.3.

Example 59: 3,6,8,9-tetramethyl-5-(o-tolyl)furo[3,2-g]quinolin-7(8H)-one

For the synthesis of building block 2-methyl-3-(methylamino)phenol, cf.Example 34.

The title compound was synthesized from 2-methyl-3-(methylamino)phenol(0.5 mmol) and methyl 2-methyl-3-(o-tolyl)-3-oxopropanoate according toSP-3 (SP-3A, 1^(st) step: heating to 170° C. for 2.5 h under microwaveirradiation; SP-3A, 2^(nd) step: heating to 150° C. for 1 h undermicrowave irradiation; preparative TLC, eluent2—95:5; SP-3C, 1^(st)step: heating to 100° C. for 1 h under microwave irradiation,partitioning between H₂O and CH₂Cl₂; SP-3C, 2^(nd) step: reaction time 1h, purification by preparative TLC, eluent2—95:5), overall yield 4%. ¹HNMR (300 MHz, CDCl₃): δ=1.92 (3H, s, Me), 2.02 (3H, s, Me), 2.06 (3H, d,Me), 2.85 (3H, s, Me), 3.97 (3H, s, NMe), 6.87 (1H, s, Ar—H), 7.07 (1H,d, Ar—H), 7.29-7.42 (4H, m, Ar—H); [M+H]⁺ (HPLC/MS): 332.3.

Example 60:5-(2-chlorophenyl)-3,6,8,9-tetramethylfuro[3,2-g]quinolin-7(8H)-one

For the synthesis of building block 2-methyl-3-(methylamino)phenol, cf.Example 34.

The title compound was synthesized from 2-methyl-3-(methylamino)phenol(3.3 mmol) and methyl 3-(2-chlorophenyl)-2-methyl-3-oxopropanoateaccording to SP-3 (SP-3A: preparative TLC, eluent2—95:5; SP-3C, 1^(st)step: reaction time 2 h, partitioning between H₂O and CH₂Cl₂; SP-3C,2^(nd) step: reaction time 1 h, purification by consecutive preparativeTLC, eluent3—3:2 then eluent2—98:2), overall yield 1%. ¹H NMR (300 MHz,d6-DMSO): δ=1.80 (3H, s, Me), 2.01 (3H, d, Me), 2.83 (3H, s, Me), 3.87(3H, s, NMe), 6.75 (1H, s, Ar—H), 7.35 (1H, m, Ar—H), 7.52-7.61 (2H, m,Ar—H), 7.71 (1H, m, Ar—H), 7.79 (1H, d, Ar—H); [M+H]⁺ (HPLC/MS): 352.3.

Example 61:5-(2-fluorophenyl)-3,6,8,9-tetramethylfuro[3,2-g]quinolin-7(8H)-one

For the synthesis of building block 2-methyl-3-(methylamino)phenol, cf.Example 34.

The title compound was synthesized from 2-methyl-3-(methylamino)phenol(3.3 mmol) and ethyl 3-(2-fluorophenyl)-2-methyl-3-oxopropanoateaccording to SP-3 (SP-3A: preparative TLC, eluent2—95:5; SP-3C, 1^(st)step: reaction time 2 h, partitioning between H₂O and CH₂Cl₂; SP-3C,2^(nd) step: reaction time 1 h, purification by consecutive preparativeTLC, eluent3—3:2 then eluent2—98:2), overall yield 1%. ¹H NMR (300 MHz,d6-DMSO): δ=1.85 (3H, s, Me), 2.02 (3H, d, Me), 2.82 (3H, s, Me), 3.86(3H, s, NMe), 6.89 (1H, s, Ar—H), 7.35 (1H, td, Ar—H), 7.40-7.48 (2H, m,Ar—H), 7.62 (1H, m_(C), Ar—H), 7.79 (1H, d, Ar—H); [M+H]⁺ (HPLC/MS):336.3.

Example 62:5-(2-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one

This compound was synthesized from methyl3-(2-methoxypyridin-3-yl)-2-methyl-3-oxopropanoate and2-methylresorcinol in 5% yield according to SP-1A (4.0 mmol; preparativeTLC, eluent2—95:5), followed by SP-1B-2 using 2.6 eq. chloroacetone (d2)(reaction time step 1=1 h, step 2=1 h; preparative TLC, eluent2—95:5).¹H NMR (300 MHz, d6-DMSO): δ=1.83 (3H, s, Me), 2.07 (3H, d, Me), 2.54(3H, s, Me), 3.83 (3H, s, OMe), 6.84 (1H, s, Ar—H), 7.25 (1H, dd, Ar—H),7.73 (1H, dd, Ar—H), 7.85 (1H, d, Ar—H), 8.41 (1H, dd, Ar—H); [M+H]⁺(HPLC/MS): 336.3.

Example 63:5-(4-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one

This compound was synthesized from methyl3-(4-methoxypyridin-3-yl)-2-methyl-3-oxopropanoate and2-methylresorcinol in 2% yield according to SP-1A (2.0 mmol; preparativeTLC, eluent2—95:5), followed by SP-1B-2 using 2.6 eq. chloroacetone (d2)(reaction time step 1=2 h, consecutive preparative TLC, eluent3—3:2 theneluent2—95:5; step 2=1 h; preparative TLC, eluent2—95:5). ¹H NMR (300MHz, d6-DMSO): δ=1.84 (3H, s, Me), 2.07 (3H, d, Me), 2.54 (3H, s, Me),3.82 (3H, s, OMe), 6.84 (1H, s, Ar—H), 7.34 (1H, d, Ar—H), 7.85 (1H, d,Ar—H), 8.31 (1H, s, Ar—H), 8.67 (1H, d, Ar—H); [M+H]⁺ (HPLC/MS): 336.2.

Example 64:5-(2-methoxypyridin-3-yl)-3,6,8,9-tetramethylfuro[3,2-g]quinolin-7(8H)-one

For the synthesis of building block 2-methyl-3-(methylamino)phenol, cf.Example 34.

The title compound was synthesized from 2-methyl-3-(methylamino)phenol(3.6 mmol) and methyl 3-(2-methoxypyridin-3-yl)-2-methyl-3-oxopropanoateaccording to SP-3 (SP-3A: preparative TLC, eluent2—95:5; SP-3C, Pt step:reaction time 2 h, partitioning between H₂O and CH₂Cl₂; SP-3C, 2^(nd)step: reaction time 1 h, purification by preparative TLC, eluent3—3:2),overall yield 1%. ¹H NMR (300 MHz, d6-DMSO): δ=1.80 (3H, s, Me), 2.03(3H, d, Me), 2.82 (3H, s, Me), 3.78 (3H, s, OMe), 3.85 (3H, s, NMe),6.84 (1H, s, Ar—H), 7.21 (1H, dd, Ar—H), 7.64 (1H, dd, Ar—H), 7.78 (1H,d, Ar—H), 8.37 (1H, dd, Ar—H); [M+H]⁺ (HPLC/MS): 349.3.

Patch-Clamp Assay for Inhibitory Activity on Kv1.3

For a description of a Kv1.3 patch-clamp assay, see Grissmer et al.,Mol. Pharmacol. 1994, 45, 1227; whole cell patch-clamp recording wasperformed with n≥2 individual experiments at each compound concentrationusing different cells. Three or more different concentrations weredetermined per dose response curve. IC₅₀ as calculated therefrom isshown in Table 1.

TABLE 1 Activity range of specific compounds of the invention on Kv1.3Patch-clamp IC₅₀(Kv1.3) values: + = 1501-3000 nM; ++ = 501-1500 nM; +++≤ 500 nM Note that examples 26-34, 36, 40, 49, 51, 52, 54-56, 59-61 and64 are not part of the present invention and serve as illustrativeexamples. Ex Structure IC₅₀  1

+++  2

+  3

+  4

+  5

+++  6

++  7

+++  8

+++  9

+++ 10

+++ 11

+++ 12

+ 13

+ 14

+ 15

+ 16

+++ 17

++ 18

++ 19

++ 20

++ 21

++ 22

++ 23

+ 24

++ 25

+++ 26

+++ 27

++ 28

++ 29

+ 30

+++ 31

+++ 32

+ 33

+++ 34

+++ 35

++ 36

+++ 37

++ 38

++ 39

+ 40

+++ 41

+++ 42

++ 43

+++ 44

+ 45

+ 46

+ 47

+ 48

++ 49

+++ 50

+ 51

++ 52

++ 53

+++ 54

+++ 55

++ 56

+ 57

+ 58

++ 59

++ 60

+++ 61

+++ 62

++ 63

+ 64

+T Cell Proliferation Assay (in Analogy to Bioorg. Med. Chem. Lett. 2009,19, 2299)

Peripheral blood mononuclear cells (PBMC) from healthy human donors wereisolated by centrifugation over a density gradient in an aqueoussolution, comprising a high molecular weight polysaccharide and sodiumdiatrizionate, and having a density of 1.077±0.001 (Ficoll-Hypaque bySigma-Aldrich, Germany; according to manufacturer's instructions).Purified PBMC were washed twice with PBS and resuspended in RPMI1640culture medium (Gibco-Life Technologies) supplemented with 10% heatinactivated fetal calf serum, 1.5 mM L-glutamine, 100 U penicillin/ml,and 100 mg streptomycin/ml (all from PAA-GE Healthcare). Forstimulation, PBMC were seeded at 1×10⁵ cells/well, incubated withTRAM-34 (5 μM) and the test compounds for 4 h and activated with 50ng/ml anti-CD3 (from eBioscience). After 48 hours proliferation wasmeasured using a BrdU based cell proliferation ELISA according to themanual. IC₅₀ as calculated therefrom is shown in Table 2.

TABLE 2 Activity range of specific compounds of the invention within theT-cell assay Example IC₅₀(BrdU) 1 + 5 ++ 7 ++ 9 +++ 10 +++ 11 ++ 16 +++25 +++ 26 +++ 30 ++ 31 +++ 34 ++ 37 + 40 +++ 41 ++ 43 ++ 49 + 53 ++ 54 +55 + IC₅₀(BrdU incorporation): + = 3.1-15.0 μM; ++ = 1.3-3.0 μM; +++ ≤1.2 μM Note that Examples 26-34, 40, 49, 54 and 55 are not part of thepresent invention and serve as illustrative examples.Pristane-induced arthritis (PIA) model:

Arthritis was induced in female Dark Agouti rats by intradermalinjection of 150 μL/rat pristane into the base of the tail on DAYO,according to Vingsbo et al., Am. J. Pathol. 1996, 149, 1675. Compoundtreatment was started on DAY16 and continued until DAY30, dosing Example53 at 60 mg/kg, p.o., sid, and Example 34 at 45 mg/kg, p.o., bid, eachin a lipophilic formulation. As a positive control, methotrexate (MTX)was dosed i.p., sid, with 0.05 mg/kg, also starting DAY16. Arthritisdevelopment was monitored daily by a macroscopic scoring system for thefour limbs ranging from 0 to 4 (0=no visible effects of arthritis;1=edema and/or erythema of one digit; 2=edema and/or erythema of twojoints; 3=edema and/or erythema of more than two joints; 4=severearthritis of the entire paw and digits, associated with ankylosis anddeformity of the paw.), resulting in an Arthritic Index (AI) reflectingthe sum of scores of all 4 limbs per rat (maximum AI=16). Both treatmentregimens resulted in significant amelioration of arthritis asillustrated in FIG. 1.

Disease induction in saline-treated and vehicle-treated control animalsreached a maximum of AI around 14. MTX-treatment resulted in a diseasestabilization around AI=8.7 (p=0.001). Treatment with Example 53decreased the AI down to around 10.4 (p=0.01) and with Example 34 downto AI around 9.1 (p<0.001).

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 illustrates the results for the Pristane-induced arthritis (PIA)model.

1-15. (canceled)
 16. A method for treating a disease or medicalcondition in which inhibiting the voltage-gated potassium channel Kv1.3is beneficial, comprising administering to a subject in need thereof aneffective amount of a compound of formula (II) or a pharmaceuticallyacceptable salt or solvate thereof,

wherein A¹ is C—R⁸; A² is C—R³; A³ is C—R⁹; A⁴ and A⁵ and A⁶ areindependently N or C—R¹; R¹ is hydrogen, (C₁-C₃)alkyl, halogen,(C₁-C₃)alkoxy, or (C₁-C₃)haloalkyl; R² is halogen, or (C₁-C₃)alkyl; R³is hydrogen, (C₁-C₃)alkyl, NR⁴R⁵, (C₁-C₃)alkyl-NR⁴R⁵, or cyano, R⁴ andR⁵ are independently hydrogen, (C₃-C₅)cycloalkyl,(C₃-C₅)heterocycloalkyl or (C₁-C₃)alkyl, or R⁴ and R⁵ together with thenitrogen atom to which they are attached form a 5- to 7-memberedheterocyclic ring optionally comprising in addition to theaforementioned nitrogen atom a further heteroatom, which is O or NR⁶, R⁶is hydrogen, methyl, acetyl or formyl; Y is O; R⁸ is —CH₃,(C₃-C₅)cycloalkyl or (C₃-C₅)heterocycloalkyl; and R⁹ is hydrogen,(C₁-C₃)alkyl or (C₁-C₃)alkoxy.
 17. The method according to claim 16,wherein in the compound of formula (II) or in the pharmaceuticallyacceptable salt or solvate thereof, R⁸ is —CH₃.
 18. The method accordingto claim 16, wherein in the compound of formula (II) or in thepharmaceutically acceptable salt or solvate thereof, at least one of thefollowing conditions is fulfilled: 1) R² is halogen, or 2) R³ is NR⁴R⁵or cyano, 3) A⁴ or A⁵ or A⁶ is N.
 19. The method according to claim 16,wherein in the compound of formula (II) or in the pharmaceuticallyacceptable salt or solvate thereof, one of A⁴ and A⁵ and A⁶ is N and theothers are N or C—R¹.
 20. The method according to claim 16, wherein inthe compound of formula (II) or in the pharmaceutically acceptable saltor solvate thereof, R⁸ is (C₃-C₅)cycloalkyl or (C₃-C₅)heterocycloalkyl.21. The method according to claim 16, wherein in the compound of formula(II) or in the pharmaceutically acceptable salt or solvate thereof, R⁸is methyl; R⁹ is methyl; R¹ is hydrogen; R² is methyl; and R³ ishydrogen.
 22. The method according to claim 16, wherein the followingcompound

wherein A⁴ and A⁵ and A⁶ are independently N or C—R¹, and R¹ ishydrogen, (C₁-C₃)alkyl, halogen, (C₁-C₃)alkoxy, or (C₁-C₃)haloalkyl orthe pharmaceutically acceptable salt thereof is administered.
 23. Themethod according to claim 16, wherein the compound of formula (II) orthe pharmaceutically acceptable salt or solvate thereof is in apharmaceutical composition further comprising a pharmaceuticallyacceptable carrier or diluent.
 24. The method according to claim 16,wherein the compound of formula (II) or the pharmaceutically acceptablesalt thereof is administered.
 25. The method according to claim 16,wherein said disease or medical condition is selected from the groupconsisting of psoriasis, psoriatric arthritis, autoimmune thyroiditis,Hashimoto's disease, Grave's disease, rheumatoid arthritis, vitiligo,Crohn's disease, ulcerative colitis, inflammatory bowel disease,ankylosing spondylitis (Morbus Bechterew), periodontal disease, diabetestype I, multiple sclerosis, systemic lupus erythematosus,anti-glomerular basement membrane glomerulonephritis, rapidlyprogressive glomerulonephritis, advanced chronic renal failure, chronickidney disease, renal fibrosis, uveitis, Pars planitis, asthma,Pemphigus foliaceus, inclusion body myositis, dermatomyositis,scleroderma, Behcet disease, atopic dermatitis, allergic dermatitis,irritant contact dermatitis, Lichen planus, Sjögren's syndrome,Graft-versus-Host-Reaction, Host-versus-Graft-Reaction, transplantrejection, end-stage renal disease, vascularized compositeallotransplantation rejection, alopecia areata, inflammatory boneresorption disease, anti-neutrophil cytoplasmic autoantibody-associatedvasculitis, osteoarthritis, diseases associated with intimalhyperplasia, breast cancer, leukemia, human lung adenocarcinoma,cutaneous T-cell lymphoma, chronic lymphocytic leukemia, osteosarcoma,neuroblastoma, ovarian cancer, melanoma, neuroinflammatory disorders,neurodegeneration, HIV-1-associated neurocognitive disorders (HAND),microglia-induced oxidative stress in Alzheimer's disease, obesity,insulin resistance, restenosis/neointimal hyperplasia, atherosclerosis,arteriosclerotic vascular disease, acute coronary syndrome, acuteischemic stroke, and hypertension.
 26. A method for treating a diseaseor medical condition in which inhibiting the voltage-gated potassiumchannel Kv1.3 is beneficial, comprising administering to a subject inneed thereof an effective amount of a compound of formula (II) or apharmaceutically acceptable salt or solvate thereof,

wherein A¹ is C—R⁸; A² is C—R³; A³ is C—R⁹; A⁴ and A⁵ and A⁶ areindependently N or C-12¹; R¹ is hydrogen, methyl, chloro, fluoro,methoxy, ethoxy or trifluoromethyl; R² is hydrogen, bromo or methyl; R³is hydrogen, methyl, morpholinyl, morpholinomethyl, N-methylaminomethyl,N,N-dimethylaminomethyl or cyano; Y is O; R⁸ is methyl or cyclopropyl;and R⁹ is hydrogen, methyl or methoxy; with the proviso that thefollowing compounds are excluded:3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,2,3,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one, and2,3-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one.
 27. The methodaccording to claim 26, wherein in the compound of formula (II) or in thepharmaceutically acceptable salt or solvate thereof, R² is hydrogen ormethyl; and R³ is hydrogen, morpholinyl, morpholinomethyl,N,N-dimethylaminomethyl or cyano.
 28. The method according to claim 26,wherein in the compound of formula (II) or in the pharmaceuticallyacceptable salt or solvate thereof, R⁸ is methyl; R⁹ is methyl; R¹ ishydrogen or methoxy; R² is hydrogen or methyl; and R³ is hydrogen,methyl or N-methylaminomethyl.
 29. The method according to claim 26,wherein the compound of formula (II) or the pharmaceutically acceptablesalt or solvate thereof is in a pharmaceutical composition furthercomprising a pharmaceutically acceptable carrier or diluent.
 30. Themethod according to claim 26, wherein the compound of formula (II) orthe pharmaceutically acceptable salt thereof is administered.
 31. Themethod according to claim 26, wherein said disease or medical conditionis selected from the group consisting of psoriasis, psoriatricarthritis, autoimmune thyroiditis, Hashimoto's disease, Grave's disease,rheumatoid arthritis, vitiligo, Crohn's disease, ulcerative colitis,inflammatory bowel disease, ankylosing spondylitis (Morbus Bechterew),periodontal disease, diabetes type I, multiple sclerosis, systemic lupuserythematosus, anti-glomerular basement membrane glomerulonephritis,rapidly progressive glomerulonephritis, advanced chronic renal failure,chronic kidney disease, renal fibrosis, uveitis, Pars planitis, asthma,Pemphigus foliaceus, inclusion body myositis, dermatomyositis,scleroderma, Behcet disease, atopic dermatitis, allergic dermatitis,irritant contact dermatitis, Lichen planus, Sjögren's syndrome,Graft-versus-Host-Reaction, Host-versus-Graft-Reaction, transplantrejection, end-stage renal disease, vascularized compositeallotransplantation rejection, alopecia areata, inflammatory boneresorption disease, anti-neutrophil cytoplasmic autoantibody-associatedvasculitis, osteoarthritis, diseases associated with intimalhyperplasia, breast cancer, leukemia, human lung adenocarcinoma,cutaneous T-cell lymphoma, chronic lymphocytic leukemia, osteosarcoma,neuroblastoma, ovarian cancer, melanoma, neuroinflammatory disorders,neurodegeneration, HIV-1-associated neurocognitive disorders (HAND),microglia-induced oxidative stress in Alzheimer's disease, obesity,insulin resistance, restenosis/neointimal hyperplasia, atherosclerosis,arteriosclerotic vascular disease, acute coronary syndrome, acuteischemic stroke, and hypertension.
 32. A method for treating a diseaseor medical condition in which inhibiting the voltage-gated potassiumchannel Kv1.3 is beneficial, comprising administering to a subject inneed thereof an effective amount of a compound selected from:5-(2-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,5-(3-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,5-(2-chlorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-5-(3-(trifluoromethyl)phenyl)-7H-furo[3,2-g]chromen-7-one,5-(2-fluorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,5-(3-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,5-(2-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,5-(2-fluorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,5-(2-ethoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,5-(2-chlorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-2-morpholino-5-phenyl-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,3,9-dimethyl-2-(morpholinomethyl)-5-phenyl-7H-furo[3,2-g]chromen-7-one,2-((dimethylamino)methyl)-3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3-methyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one,3-methyl-5-(m-tolyl)-7H-furo[3,2-g]chromen-7-one,5-(2-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,5-(3-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,5-(2-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,5-(3-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,9-methoxy-3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3-cyclopropyl-9-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3-cyclopropyl-6,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,2-((dimethylamino)methyl)-3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3,6,9-trimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-5-(pyridin-2-yl)-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one,5-(2-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,and5-(4-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,or a pharmaceutically acceptable salt or solvate thereof.
 33. The methodaccording to claim 32, wherein the following compound

or the pharmaceutically acceptable salt thereof is administered.
 34. Themethod according to claim 32, wherein the following compound

or the pharmaceutically acceptable salt thereof is administered.
 35. Themethod according to claim 32, wherein the compound selected from:5-(2-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,5-(3-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,5-(2-chlorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-5-(3-(trifluoromethyl)phenyl)-7H-furo[3,2-g]chromen-7-one,5-(2-fluorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,5-(3-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,5-(2-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,5-(2-fluorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,5-(2-ethoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,5-(2-chlorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-2-morpholino-5-phenyl-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,3,9-dimethyl-2-(morpholinomethyl)-5-phenyl-7H-furo[3,2-g]chromen-7-one,2-((dimethylamino)methyl)-3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3-methyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one,3-methyl-5-(m-tolyl)-7H-furo[3,2-g]chromen-7-one,5-(2-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,5-(3-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,5-(2-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,5-(3-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,9-methoxy-3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3-cyclopropyl-9-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3-cyclopropyl-6,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,2-((dimethylamino)methyl)-3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3,6,9-trimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-5-(pyridin-2-yl)-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one,5-(2-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,and5-(4-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,or the pharmaceutically acceptable salt or solvate thereof is in apharmaceutical composition further comprising a pharmaceuticallyacceptable carrier or diluent.
 36. The method according to claim 32,wherein the compound selected from:5-(2-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,5-(3-methoxyphenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,5-(2-chlorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-5-(3-(trifluoromethyl)phenyl)-7H-furo[3,2-g]chromen-7-one,5-(2-fluorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,5-(3-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,5-(2-methoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,5-(2-fluorophenyl)-3,9-dimethyl-7H-furo[3,2-g]chromen-7-one,3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,5-(2-ethoxyphenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,5-(2-chlorophenyl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-2-morpholino-5-phenyl-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,3,9-dimethyl-2-(morpholinomethyl)-5-phenyl-7H-furo[3,2-g]chromen-7-one,2-((dimethylamino)methyl)-3,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3-methyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one,3-methyl-5-(m-tolyl)-7H-furo[3,2-g]chromen-7-one,5-(2-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,5-(3-methoxyphenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,5-(2-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,5-(3-chlorophenyl)-3-methyl-7H-furo[3,2-g]chromen-7-one,9-methoxy-3-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3-cyclopropyl-9-methyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3-cyclopropyl-6,9-dimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-7-oxo-5-phenyl-7H-furo[3,2-g]chromene-2-carbonitrile,2-((dimethylamino)methyl)-3,6,9-trimethyl-5-phenyl-7H-furo[3,2-g]chromen-7-one,3,6,9-trimethyl-5-(pyridin-3-yl)-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-5-(pyridin-2-yl)-7H-furo[3,2-g]chromen-7-one,3,9-dimethyl-5-(o-tolyl)-7H-furo[3,2-g]chromen-7-one,5-(2-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,and5-(4-methoxypyridin-3-yl)-3,6,9-trimethyl-7H-furo[3,2-g]chromen-7-one,or the pharmaceutically acceptable salt thereof is administered.
 37. Themethod according to claim 32, wherein said disease or medical conditionis selected from the group consisting of psoriasis, psoriatricarthritis, autoimmune thyroiditis, Hashimoto's disease, Grave's disease,rheumatoid arthritis, vitiligo, Crohn's disease, ulcerative colitis,inflammatory bowel disease, ankylosing spondylitis (Morbus Bechterew),periodontal disease, diabetes type I, multiple sclerosis, systemic lupuserythematosus, anti-glomerular basement membrane glomerulonephritis,rapidly progressive glomerulonephritis, advanced chronic renal failure,chronic kidney disease, renal fibrosis, uveitis, Pars planitis, asthma,Pemphigus foliaceus, inclusion body myositis, dermatomyositis,scleroderma, Behcet disease, atopic dermatitis, allergic dermatitis,irritant contact dermatitis, Lichen planus, Sjögren's syndrome,Graft-versus-Host-Reaction, Host-versus-Graft-Reaction, transplantrejection, end-stage renal disease, vascularized compositeallotransplantation rejection, alopecia areata, inflammatory boneresorption disease, anti-neutrophil cytoplasmic autoantibody-associatedvasculitis, osteoarthritis, diseases associated with intimalhyperplasia, breast cancer, leukemia, human lung adenocarcinoma,cutaneous T-cell lymphoma, chronic lymphocytic leukemia, osteosarcoma,neuroblastoma, ovarian cancer, melanoma, neuroinflammatory disorders,neurodegeneration, HIV-1-associated neurocognitive disorders (HAND),microglia-induced oxidative stress in Alzheimer's disease, obesity,insulin resistance, restenosis/neointimal hyperplasia, atherosclerosis,arteriosclerotic vascular disease, acute coronary syndrome, acuteischemic stroke, and hypertension.